<title>1. INTRODUCTION</title> <p>Di(2-ethylhexyl)phthalate
(DEHP) a plasticizer around the world, suggesting that many
people come across this chemical every day. Animal studies showed that this
chemical is a nongenotoxic carcinogen. Metabolites of DEHP, mono- and
dicarboxylic acids, transactivate peroxizome proliferator-activated receptor <italic>α</italic> (PPAR<italic>α</italic>),
which has been thought to result in nongenotoxic carcinogenesis [##REF##14727734##1##, ##REF##8817083##2##]. However, the latest studies also
showed the involvement of non-PPAR<italic>α</italic> pathways; multiple pathways might be
involved in the pathway of DEHP-induced carcinogenicity [##REF##16954067##3##]. There are species differences in
the functional activation or constitutive expression of rodent and human PPAR<italic>α</italic>,
and that in humans is thought to be less active and expressive than those of
rodents. Recently, inflammation-related carcinogenesis has drawn attention [##REF##15385993##4##, ##REF##15329734##5##]. PPAR<italic>α</italic> is involved not only in
the induction of target genes such as <italic>β</italic>-oxidation enzymes of fatty acids but also in anti-inflammation
signaling [##REF##14999402##6##, ##REF##2129546##7##], suggesting that PPAR<italic>α</italic> also may protect
against carcinogenesis. Species differences in lipase activity (DEHP-metabolizing
enzyme) among mice, rats, and marmosets have been also reported recently [##REF##15798888##8##], suggesting that this kinetic
difference should be considered in the species differences in DEHP-induced
carcinogenesis. In this review, we focused on DEHP-induced hepatic
carcinogenesis in relation to PPAR<italic>α</italic>-dependent and PPAR<italic>α</italic>-independent pathways, and discussed
the science policy.</p>
<title>9. CONCLUSIONS</title> <p>As mentioned above, some studies suggest
the possibility of DEHP tumorigenesis via a non-PPAR<italic>α</italic> pathway although DEHP also
exerts adverse effects via PPAR<italic>α</italic>-dependent pathway. Since there are species
differences regarding expression levels, cellular context, and function of
PPAR<italic>α</italic> as well as metabolism enzyme activity of DEHP, it is difficult to
extrapolate the results from rodents to humans in terms of risk. Recently,
hPPAR<italic>α</italic> mice have been developed, which may help to solve these differences. Re-evaluation
of the risk of DEHP carcinogenicity may well be warranted if the previous
decisions were based on only PPAR<italic>α</italic>-dependent mechanisms.</p>
<p>Recommended by Dipak Panigrahy</p> <p>Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer and a potentially nongenotoxic carcinogen. Its mechanism had been earlier proposed based on peroxisome proliferator-activated receptor <italic>α</italic> (PPAR<italic>α</italic>) because metabolites of DEHP are agonists. However, recent evidence also suggests the involvement of non-PPAR<italic>α</italic> multiple pathway in DEHP-induced carcinogenesis. Since there are differences in the function and constitutive expression of PPAR<italic>α</italic> among rodents and humans, species differences are also thought to exist in the carcinogenesis. However, species differences were also seen in the lipase activity involved in the first step of the DEHP metabolism, which should be considered in DEHP-induced carcinogenesis. Taken together, it is very difficult to extrapolate the results from rodents to humans in the case of DEHP carcinogenicity. However, PPAR<italic>α</italic>-null mice or mice with human PPAR<italic>α</italic> gene have been developed, which may lend support to make such a difficult extrapolation. Overall, further mechanical study on DEHP-induced carcinogenicity is warranted using these mice.</p>
<title>2. PPARs</title> <p>PPARs are
involved in a member of the nuclear hormone receptor superfamily, and consist
of three subunits: PPAR<italic>α</italic>, PPAR<italic>β</italic>/<italic>δ</italic>, and PPAR<italic>γ</italic> [##REF##10839530##9##]. These three isoforms have been
identified at the organ-specific level. In the respective organ, PPARs function
as transcription factors through the classic ligand-dependent nuclear hormone
receptor mechanism. Upon binding to their ligands, PPARs undergo conformational
changes that allow corepressor release [##REF##16322072##10##]. The PPAR-ligand complex binds to
direct repeat 1 elements or peroxisome proliferator response elements (PPREs),
usually located upstream of the target genes, which results in the induction of
fatty acid transport and metabolism, glucose metabolism, and also elicitation
of anti-inflammatory effects [##REF##14999402##6##, ##REF##17261671##11##].</p> <p>As one of the three isoforms, PPAR<italic>α</italic> is mainly expressed in
organs that are critical in fatty acid catabolism, such as liver, heart, and
kidney [##REF##2129546##7##]. Thus, this nuclear receptor is
primarily involved in the regulation of fatty acid metabolism. In addition to
this function, PPAR<italic>α</italic>
also has various functions including the promotion of gluconeogenesis,
lipogenesis, ketogenesis, and anti-inflammatory effects [##REF##14999402##6##].</p> <title>3. PPAR<italic>α</italic> LIGANDS</title> <p>The ligands of PPAR<italic>α</italic> represent a diverse group of
chemicals including not only endogenous ligands but also exogenous synthetic
ligands with a high likelihood of clinical, occupational, and environmental
exposure of humans to chemicals [##REF##14727734##1##, ##REF##12580534##12##]. The primary endogenous ligands
are fatty acids, mainly the 18–20 carbon polyunsaturated fatty acids and
eicosanoids [##REF##2129546##7##, ##REF##1312391##13##–##REF##18191967##17##]. As exogenous ligands, fibrates
and thiazolidinediones are involved. Additionally, the general population is
exposed to environmental chemicals such as plasticizers (e.g., phthalates),
solvents (e.g., tetrachloroethylene and trichloroethylene), perfluorooctanoic
acid and herbicides (e.g., 2, 4-dichlorophenoxyacetic acid, diclofop-methyl,
haloxyfop, lactofen, and oxidiazon).</p> <p>Of these ligands, the toxicity of DEHP is well
established in relation to PPAR<italic>α</italic>. This chemical is used as a
plasticizer to improve the plasticity and elasticity of polyvinyl chloride
products that have become ubiquitous in our daily living. These products are
widely used in building materials, wallpaper and flooring, wire covering, vinyl
sheeting for agriculture, food packages, and medical devices such as
intravenous and hemodialysis tubing and blood bags. The recent production of
DEHP in Japan
has approached 14 000 tons per year, which accounts for about 54% of all
plasticizers used [##REF##17261671##11##]. It is noted that mono- and dicarboxylic acid
metabolites of DEHP, not DEHP itself, act as ligands for PPAR<italic>α</italic>
[##REF##10581215##18##] and have potentially adverse
effects on liver, kidney, heart, and reproductive organs though monocarboxylic
acid, mono(2-ethylhexyl) phthalate (MEHP), also binds to PPAR<italic>γ</italic> [##REF##10581215##18##].</p> <title>4. SPECIES DIFFERENCES IN PPAR<italic>α</italic>
</title> <p>Since there are
species differences in the toxicity of PPAR<italic>α</italic> agonists, the expression levels or
functions of the receptor are thought to be different among species. Several
explanations for the species differences in response to the ligands have been
suggested [##UREF##1##19##, ##UREF##2##20##]. One of the major factors was considered
to be due to differences in the levels of PPAR<italic>α</italic> expression [##REF##18006136##21##, ##UREF##3##22##] although other possibilities include
differences in ligand affinity between rodent and human PPAR<italic>α</italic>, differences in
cellular context of PPAR<italic>α</italic> expression, and those in PPRE sequences found upstream
of critical target genes [##REF##9827524##23##, ##REF##15976920##24##]. Indeed, PPAR<italic>α</italic> expression in
humans is about 1/10 times less than that in rodents [##REF##9443928##25##]. In addition, micro-RNA
expression regulated by PPAR<italic>α</italic> has been recently reported to be changed in
wild-type mice, but not in mice with human PPAR<italic>α</italic> gene [##REF##17438130##26##]; Wy-14,643 inhibited a micro-RNA
let-7C which is involved in suppression of tumorigenesis in wild-type mice, but
neither in PPAR<italic>α</italic>-null mice nor in mice with human PPAR<italic>α</italic> gene. Mice
with human PPAR<italic>α</italic> gene are resistant to hepatocellular proliferation though they
respond to Wy-14,643 in <italic>β</italic>-oxidation and serum triglycerides [##REF##15172993##27##]. These results suggest that the function
of the PPAR<italic>α</italic> signaling in liver proliferation and tumorigenesis by the chemical
exposure is not always similar in mice and humans.</p> <p>In regard to the species differences in
the PPREs, the lack of acyl CoA oxidase (ACO) induction in studies on liver
biopsies from humans treated with hypolipidemic drugs or primary human
hepatocytes treated with Wy-14,643 may be attributable to an inactive
functional PPRE since the sequence of a PPRE for the ACO gene from a small
number of human liver biopsy samples was found to be different from that of the
rats [##REF##10190548##28##]. However, Reddy remarked at a
panel discussion that, although the sequence of ACO gene promoter in the mouse
was also different from that in the rat, both rodents are responsive to some
peroxisome proliferators in ACO induction [##UREF##2##20##]. In addition, differences in the
ability of rodents and human PPAR to recognize and bind PPRE are unlikely since
the DNA binding domains of the human and rodent PPAR<italic>α</italic> are 100% homologous [##REF##7684926##29##, ##REF##7981125##30##]. Though characterized from only a
limited number of individuals, the prevalence in the population of defective
PPAR alleles cannot be determined at this point [##REF##8759039##31##]. The species difference in the
sequence of PPRE may not be involved in the difference in response to ligands
between rodents and humans.</p> <p>In addition to the lower expression
levels of PPAR<italic>α</italic> in human, there was a truncated, inactive form of PPAR<italic>α</italic> in
human liver, suggesting that the expression of full-length functional PPAR<italic>α</italic> was
very low. These inactive forms of PPAR<italic>α</italic> may be insufficient to bind PPRE
because PPREs may be occupied in vivo by other nuclear receptors that bind to
similar sequences, thus affecting responsiveness to ligands [##REF##9443928##25##].</p> <title>5. SPECIES DIFFERENCES IN DEHP METABOLISM</title> <p>In addition to
the species differences in PPAR<italic>α</italic> functions or expression levels, we should also
be mindful of the importance of those in the metabolism of DEHP between rodents
and humans. DEHP absorbed in the body is first metabolized by the catalytic
action of lipase to produce MEHP and 2-ethylhexanol (2-EH) [##REF##2696633##32##]. Some MEHP is then conjugated
with UDP-glucuronide by UDP-glucuronosyltransferase (UGT) and excreted in the
urine. The remaining MEHP is excreted directly in the urine or is oxidized by
cytochrome P450 4A, then further oxidized by alcohol dehydrogenase (ADH) or
aldehyde dehydrogenase (ALDH) to dicarboxylic acid or ketones. 2-EH is metabolized
mainly to carboxylic acid (mainly 2-ethylhexanoic acid (2HEA)) via 2-ethylhexanal
by catalytic action of ADH and ALDH. Thus, lipase may be an essential enzyme to
regulate the DEHP metabolism; knowing the species difference in the lipase
activity may be an important tool to clarify the species difference in
metabolism.</p> <p>Recently,
the activities of lipase, UGT, ADH, and ALDH for DEHP metabolism in several
organs were measured and compared among mice, rats, and marmosets [##REF##15798888##8##]. Marmosets were used as a
reference to human. Clear-cut species differences were seen in the activities
of the four enzymes involved in the DEHP metabolism among mice, rats, and
marmosets. The most prominent difference was observed in the lipase activity
with an almost 148- to 357-fold difference between the highest activity in mice
and the lowest in marmosets (##FIG##0##Figure 1##). These differences were comparable to
those in the kinetic parameter, <italic>Vmax.</italic> These results suggest that the constitutive levels of lipase were
greater in the mice and rats than in marmosets. Indeed, lipase-mRNA
levels in livers from mice or rats were much higher than those in marmoset (##FIG##1##Figure
2##). Thus, concentrations of MEHPs (ligands to PPAR<italic>α</italic>) in the body were
higher in mice or rats than in marmosets when the same dose of DEHP was
administered [##REF##16937134##33##].</p> <p>Besides species differences in the
constitutive levels of lipase, <italic>Km</italic> values of DEHP for lipase of marmosets
were much higher than in rats or mice, suggesting the species differences in
the DEHP affinity for lipase; the affinity of DEHP for lipase in the marmosets
may be lower than that of mice or rats. The affinity in human may be even lower
than that in primates; cumulative <sup>14</sup>C excretion in urine of African green
monkey following bolus injection of <sup>14</sup>C-DEHP leached into autologous
plasma occurred earlier than in human [##REF##7140682##34##].</p> <title>6. MECHANISM OF DEHP-INDUCED CANCER</title> <p>DEHP
causes tumors, especially in liver when chronically administered to rats and
mice [##REF##11099649##35##–##REF##12778218##39##],
similar to the other peroxisome proliferators such as Wy-14643. ##TAB##0##Table 1## shows that DEHP induces hepatic
tumors in mice and rats. From the viewpoint of percentage in feed, the lowest-observed
effect-level (LOEL) of DEHP carcinogenicity in the rat was 0.6%, and the no-observed
effect-level (NOEL) was 0.1% [##REF##8817083##2##]. In the mouse, the corresponding values may
be 0.05% for LOEL and 0.01% for NOEL because the study in which male mice were exposed
to 0.05% DEHP for 78 weeks exhibited a significant increase in the hepatic
tumor incidence rate compared with controls, but not when exposed to 0.01% DEHP
[##REF##10478855##40##].</p> <p>DEHP also has potential for carcinogenesis in
other organs; pancreatic acinar cell adenoma and mononuclear cell leukemia
incidences were significantly increased in male F344 rat but not in F344 female
rat and B6C3F1 mouse of both sexes after DEHP exposure [##REF##11099649##35##, ##REF##10828276##36##, ##REF##11560248##44##]. The reason why these cancers are not
observed in female rat has not been identified.</p> <p>Chronic
treatment with PPAR<italic>α</italic> agonist results in an increased incidence of liver tumors
which were thought to have occurred through a PPAR<italic>α</italic>-mediated mechanism as
revealed by the resistance of PPAR<italic>α</italic>-null mice to liver cancer induced by
Wy-14,643 exposure for 11 months [##REF##9395198##46##]. All the
wild-type mice fed with 0.1% Wy-14643 diet for 11 months had multiple
hepatocellular neoplasms, including adenomas and carcinomas, while thePPAR<italic>α</italic>-null
mice fed with the 0.1% Wy-14643 diet for the same duration were unaffected.
Ward et al. [##REF##9547862##47##] reported that
exposure for only six months to 12 000 ppm DEHP caused induction of peroxisomal
enzymes, liver enlargement, and histopathological increases in eosinophil
counts and peroxisomes in the cytoplasm of wild-type mice, while there were no
such toxic findings in the liver of PPAR<italic>α</italic>-null
mice. Thus, DEHP-derived carcinogenicity was thought to be mediated by PPAR<italic>α</italic>,
similar to Wy-14,643, and DEHP was considered to cause primarily
PPAR<italic>α</italic>-dependent carcinogenicity in rodents, but it is considered to be
relatively safe in humans, similar to other ligands [##REF##8817083##2##]. However, Ward
et al. [##REF##9547862##47##] could not directly
observe DEHP-derived tumors in the wild-type mice, because exposure to DEHP for 6 months may
not be sufficient to induce hepatic tumors, as suggested by Marsman et al. [##REF##3180084##48##]; they reported that DEHP
tumorigenesis required longer exposure periods than Wy-14,643.
It is doubtful whether DEHP definitively induces hepatic tumors via PPAR<italic>α</italic>.</p> <p>As mentioned
above, the following simple mechanism has been proposed for the DEHP-induced
hepatocarcinogenesis; when DEHP was administered to rats and mice, the chemical
caused an increase in cell proliferation and peroxisome proliferation [##REF##10388618##49##]. The latter
is accompanied by an increase in both peroxisomal and mitochondrial fatty acid
metabolizing enzymes such as ACO. As a byproduct of fatty acid oxidation,
enzymes involved with <italic>β</italic>-oxidation generate H<sub>2</sub>O<sub>2</sub>,
resulting in elevated oxidative stress. DEHP also causes an increase in proinflammatory
cytokines and inhibition of apoptosis [##REF##8817083##2##, ##REF##15976920##24##].</p> <p>DEHP-induced
liver carcinogenesis in rodents, however, appears to involve more complex
pathways as described in the following events whereby various combinations of
the molecular signals and multiple pathways may be involved [##REF##16954067##3##]. DEHP is
metabolized to bioactive metabolites which are absorbed and distributed
throughout the body; they might induce PPAR<italic>α</italic>-independent activation of
macrophages and production of oxidants, and also activate PPAR<italic>α</italic> and sustained
induction of target genes. The inductions lead to enlargement of hepatocellular
organelles, an increase in cell proliferation, a decrease in apoptosis, sustained
hepatomegaly, chronic low-level oxidative stress and accumulation of DNA damage,
and selective clonal expansion of the initiated cells. Finally, preneoplastic
nodules might be induced and might result in adenomas and carcinoma.</p> <p>Peraza et al.
[##REF##16322072##10##] also suggest that PPAR<italic>α</italic>
is the only receptor in PPARs that is known to mediate carcinogenesis, while
the prevailing evidence suggests that PPAR<italic>β</italic>, PPAR<italic>γ</italic>, and their ligands appear to
be tumor modifiers that inhibit carcinogenesis, albeit there is still
controversy in the field. Melnick [##REF##11401753##50##] also
addressed non-PPAR<italic>α</italic> mechanisms for DEHP-induced carcinogenicity as follows. (1)
Peroxisome
proliferator-induced tumorigenesis is related to the genes involved in cellular
proliferations of, for example, p38 mitogen-activated protein kinase, which is
not involved in peroxisome proliferations [##REF##12151621##51##]. (2) DEHP and other peroxisome
proliferators stimulated growth regulatory pathways such as immediate early
genes for carcinogenesis (c-jun, c-fos, junB, egr-1), mitogen-activated protein
kinase, extracellular signal-regulated kinase, and phosphorylation of p38,
which were dissociated from PPAR<italic>α</italic> activation in rat
primary cultures [##REF##11858942##52##–##REF##8352887##54##]. These findings also support the
view that peroxisome proliferators, including DEHP, may have the potential for
tumorigenesis via non-PPAR<italic>α</italic> signal pathways.</p> <p>In recent
years, an inflammation-associated model of cancers has been given attention [##REF##15385993##4##, ##REF##15329734##5##].
PPAR<italic>α</italic> exerts anti-inflammation effects by repressing nuclear factor kappa B
(NF<italic>κ</italic>B) [##REF##16378501##55##], which
inhibits inflammation signaling and subsequent cancer [##REF##15385993##4##].</p> <p>Ito et al. [##REF##17575397##45##]
proposed possibility of DEHP tumorigenesis via a non-PPAR<italic>α</italic> pathway using PPAR<italic>α</italic>-null mice. They compared DEHP-induced
tumorigenesis in wild-type and PPAR<italic>α</italic>-null mice treated
for 22 months with diets containing 0, 0.01, or 0.05% DEHP. Surprisingly, the
incidence of liver tumors was higher in PPAR<italic>α</italic>-null
mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild-type mice (10%), while the incidence was 0% in wild-type miceand 4% in PPAR<italic>α</italic>-null
mice without DEHP exposure. The levels of 8-hydroxydeoxyguanosine increased
dose-dependently in mice of both genotypes, but the degree of increase was
higher in PPAR<italic>α</italic>-null mice than in
wild-type mice. NF<italic>κ</italic>B
levels also significantly increased in a dose-dependent manner in PPAR<italic>α</italic>-null mice. The proto-oncogene
c-jun-mRNA was induced, while c-fos-mRNA tended to be induced only in PPAR<italic>α</italic>-null mice fed with 0.05%
DEHP-containing diet. These results suggest that chronic low-level oxidative
stress induced by DEHP exposure may lead to the induction of inflammation
and/or the expression of proto-oncogenes, resulting in a high incidence of
tumorigenesis in PPAR<italic>α</italic>-null mice. Moderate activated PPAR<italic>α</italic> might protect from p65/p50 NF<italic>κ</italic>B inflammatory pathway caused by
chronic DEHP exposure in wild-type mice. Although cross-talk of PPAR<italic>γ</italic>,
but not PPAR<italic>α</italic>, with cyclooxygenase 2 (Cox-2), which also was related
with inflammation-induced hepatocellular carcinoma, has been suggested [##REF##16337744##56##], there was neither induction of
Cox-2 nor PPAR<italic>γ</italic> in both genotyped mice of that study (data
not shown).</p> <p>Additionally, we compared the mechanisms
of tumorigenesis between wild-type mice and PPAR<italic>α</italic>-null
mice using hepatocellular adenoma tissues of both genotyped mice [##REF##18403868##57##]. The microarray profiles showed
that the up- or downregulated genes were quite different between hepatocellular
adenoma tissues of wild-type mice and PPAR<italic>α</italic>-null
mice exposed to DEHP, suggesting that their tumorigenesis mechanisms might be
different. Interestingly, the gene expressions of apoptotic peptidase
activating factor 1 and DNA-damage-inducible 45<italic>α</italic> (Gadd45<italic>α</italic>) were increased in
the hepatocellular adenoma tissues of wild-type mice exposed to DEHP, whereas
they were unchanged in corresponding tissues of PPAR<italic>α</italic>-null mice. On the other hand, the expressions of cyclin B2
and myeloid cell leukemia sequence 1 were increased only in the hepatocellular
adenoma tissues of PPAR<italic>α</italic>-null mice.
Taken together, DEHP may induce hepatocellular adenomas, partly via suppression
of G2/M arrest regulated by Gadd45<italic>α</italic> and caspase 3-dependent apoptosis in PPAR<italic>α</italic>-null mice. However, these genes
may not be involved in tumorigenesis in wild-type mice. In contrast, the
expression level of Met was notably increased in the liver adenoma tissue of
wild-type mice, which may suggest the involvement of Met in DEHP-induced
tumorigenesis in wild-type mice. However, we could not
determine whether DEHP promoted the spontaneous liver tumor in PPAR<italic>α</italic>-null
mice because spontaneous hepatocellular tumors are known to occur in these mice
at 24 months of age [##REF##15603543##58##], while
we observed DEHP-induced tumorigenesis at 22 months of age. To clarify this,
gene expression profiles of liver tumors in the control group must be analyzed.</p> <p>Taken together,
the mechanisms of DEHP-induced carcinogenesis do not consist of only a simple
pathway such as PPAR<italic>α</italic>-mediated peroxisome proliferation as mentioned by Rusyn et
al. [##REF##16954067##3##].
PPAR<italic>α</italic>-independent pathways may also exist and, by contrast, activated PPAR<italic>α</italic> may
protect against DEHP-induced carcinogenesis. The valance of the production of
oxidative stress via the transactivation of PPAR<italic>α</italic> and subsequent DNA damages
versus the effective exertion of anti-inflammation by activating the receptor may
determine the incidence of DEHP-induced tumors.</p> <title>7. FUTURE INVESTIGATIONS</title> <p>To determine the mechanism of species
difference in response to peroxisome proliferators, a mouse line with human PPAR<italic>α</italic>
was produced and designated hPPAR<italic>α</italic>
<sup>TetOff</sup> [##REF##15172993##27##]. This mouse line expresses the
human receptor in liver in a PPAR<italic>α</italic>-null
background by placing the hPPAR<italic>α</italic> cDNA under control of the Tet-Off system of
doxycycline control with the liver-specific LAP1 (C/EBP<italic>β</italic>) promoter.
Interestingly, the hPPAR<italic>α</italic>
<sup>TetOff</sup> mice express the human PPAR<italic>α</italic> protein
at levels comparable to those
expressed in wild-type mice; so we should not need to consider the species
differences in the expression of PPAR<italic>α</italic> between mice and humans. Treatment of
this mouse line with Wy-14,643 revealed induction of genes' encoding
peroxisomal lipid-metabolizing enzymes, including ACO, bifunctional enzyme and peroxisomal
thiolase, and the fatty acid transporter CD36 at a level comparable to that in
wild-type mice, expressing native mouse PPAR<italic>α</italic>. This suggested that human PPAR<italic>α</italic>
is functionally active. Upon treatment with Wy-14,643, hPPAR<italic>α</italic>
<sup>TetOff</sup> mice also had lower levels of fasting serum total triglycerides similar to
wild-type mice. However, hPPAR<italic>α</italic>
<sup>TetOff</sup> mice did not show any
significant hepatocellular proliferation, nor did they have an induction of
cell cycle control genes, in contrast to Wy-14,643-treated wild-type mice where
a significant increase in mRNAs encoding PCNA, cMYC, cJUN, CDK1, CDK4, and
several cyclins was found after treatment with Wy-14,643. hPPAR<italic>α</italic>
<sup>TetOff</sup> mice were also found to be resistant to Wy-14,643-induced hepatocarcinogenesis
after 11 months of Wy-14,643 feeding in contrast to a 100% incidence in the
wild-type mouse group [##REF##16377806##59##].</p> <p>Another transgenic mouse line with human PPAR<italic>α</italic>
was generated that has the complete human PPAR<italic>α</italic> gene on a P1 phageartificial chromosome (PAC) genomic clone, introduced onto the mouse PPAR<italic>α</italic>-null background [##REF##17690133##60##]. This new line, designated hPPAR<italic>α</italic>
<sup>PAC</sup>,
expresses human PPAR<italic>α</italic> not only in liver but also in kidney and
heart. hPPAR<italic>α</italic>
<sup>PAC</sup> mice exhibited responses similar to wild-type mice
when treated with fenofibrate lowering of serum triglycerides and induction of
PPAR<italic>α</italic> target genes' encoding enzymes involved in fatty acid metabolism.
Treatment of hPPAR<italic>α</italic>
<sup>PAC</sup> mice with fenofibrate did not cause
significant hepatomegaly and hepatocyte proliferation similar to hPPAR<italic>α</italic>
<sup>TetOff</sup> mice, suggesting that the resistance to the hepatocellular proliferation found
in the hPPAR<italic>α</italic>
<sup>TetOff</sup> mice is not due to lack of expression of the
receptor in tissues other than liver.</p> <p>Until now, there are no reports concerning the
interaction between DEHP and hPPAR<italic>α</italic>
<sup>TetOff</sup> or hPPAR<italic>α</italic>
<sup>PAC</sup>.
Recently, we have compared the transactivation of mouse and human PPAR<italic>α</italic> by DEHP treatments
using wild-type and hPPAR<italic>α</italic>
<sup>TetOff</sup> mice (unpublished observation). A relatively
high dose of DEHP (5 mmol/kg for 2 weeks) clearly activated PPAR<italic>α</italic> in liver of
both genotyped mice, but the activation was very little in hPPAR<italic>α</italic>
<sup>TetOff</sup> mice from the standpoint of the target gene expression as well as triglyceride
levels in plasma and liver. Human PPAR<italic>α</italic> response to DEHP may be weak when sufficient human PPAR<italic>α</italic> is expressed in the
human liver. Thus, the use of the hPPAR<italic>α</italic>
<sup>TetOff</sup> mouse model is a very
valuable means to solve the species differences in the toxicity of peroxisome
proliferators. The results from the typical peroxisome proliferator (Wy-14643)
may not always be similar to those of DEHP; a study of each case is needed
using hPPAR<italic>α</italic>
<sup>TetOff</sup> mouse model.</p> <title>8. PROPOSED SCIENCE POLICY STATEMENTS</title> <p>The International Agency for Research on Cancer downgraded the level
of potential health risks of DEHP from 2b (possibly carcinogenic to humans) to 3 (not classifiable as to carcinogenicity to humans) in 2000 [##UREF##4##61##]. In
this report, DEHP carcinogenesis via PPAR<italic>α</italic> was considered not to be relevant to
humans because peroxisome proliferation had not been documented either in human
hepatocyte cultures exposed to DEHP or in the liver of nonhuman primates. This
decision has been variously argued by several scientists in the literature [##REF##11401753##50##, ##REF##15688552##62##, ##REF##14664499##63##]. In contrast, the Japan Society
for Occupational Health has maintained the 2B class of DEHP carcinogenicity
because of the obvious rodent carcinogenicity [##UREF##5##64##].</p> <p>Although the US Environmental
Protection Agency (EPA) had classified the risk for DEHP carcinogenicity as B2 (probable human carcinogen) in 1993, recently, the expert panel of EPA report has provided
the current scientific understanding of the mode(s) of action of PPAR<italic>α</italic> agonist-induced
tumors observed in rodent bioassays that are associated with PPAR<italic>α</italic> agonisms: liver
tumors in rats and mice as well as Leydig cell and pancreatic acinar cell
tumors in rats—all of which represent
limited evidence [##UREF##6##65##]. Since the key events for the mode of action, which have
been causally related to liver tumor formation, include the activation of PPAR<italic>α</italic>, perturbation of cell
proliferation and apoptosis, selective clonal expansion, and the
PPAR<italic>α</italic>-related key events included in the expression of peroxisomal genes (e.g., palmitoyl CoA oxidase and acyl CoA oxidase) and
peroxisome proliferation (i.e., an increase in
the number and size of peroxisomes) are reliable markers. Additionally, the
evidence obtained from the findings that PPARa agonists did not activate the
receptor in human cell culture or biopsy samples, and from epidemiological
studies, shows that humans are apparently refractory to the effects of a PPAR<italic>α</italic>
agonist. However, the EPA maintained the DEHP carcinogenicity criterion.</p> <p>In 2004, with regard to preclinical and clinical safety assessments
for PPAR agonists, the Food and Drug Administration recommended that, due to the prevalence of positive tumor findings of PPAR
agonists, two-year carcinogenicity studies on mice and rats are required [##UREF##7##66##].</p> <p>Although IARC changed the criterion for DEHP
carcinogenicity, other agencies did not because DEHP is a potential rodent
carcinogen of liver and the precise mechanism has not been yet understood,
though DEHP is a potentially hepatic carcinogen in rodents.</p>
<title>ACKNOWLEDGMENT</title> <p>This study was supported in part by
Grant-in-Aid for Scientific Research from the Japan Society for the Promotion
of Science (B. 14370121, 17390169).</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p> Species
differences in lipase activities (pmol/mg protein in microsomal fragment/min)
using hepatic microsomes in liver, small intestine, kidney, and lung from mice,
rats, and marmosets. Lipase activity was measured by GC/MS. Substrate
concentration (DEHP) used was 1 mM. Each white bar (6 mice), grey bar (5 rats),
or black bar (5 marmosets) represents the mean ± standard deviations. Lipase
activity was not detected in marmoset lung (under 1 pmol/mg protein/min).
Comparisons were made using analysis of variance and the Tukey-Kramer HSD post hoc
test. A logarithmic transformation was applied to lipase activities in
microsome samples from the small intestine and kidneys before Tukey-Kramer
analysis. Different letters (a, b, c) on the top of each bar in each organ indicate
that they are significantly different from each other (<italic>P</italic> &lt; .05).</p></caption></fig> <fig id="fig2" position="float"><label>Figure 2</label><caption><p>
Lipase-mRNA
levels in mice, rats, and marmosets. Each mRNA level was measured by real-time
quantitative PCR and normalized to the GAPDH-mRNA level in the same preparation.
Mouse liver mean was assigned a value of 100. Figures represent mean ± SD from 6 from mice and 5 from
rats and marmosets. Comparisons were made using analysis of variance
and the Tukey-Kramer HSD post hoc test. Different letters (a, b, c) on the top
of each bar in each organ indicate that they are significantly different from each
other (<italic>P</italic> &lt; .05).</p></caption></fig>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Primary studies on DEHP-induced carcinogenesis in mice and rats (modifying the paper reported by Huber et al. [##REF##8817083##2##]).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"> Author </th><th align="center" rowspan="2" colspan="1">
Sex </th><th align="center" rowspan="2" colspan="1"> Route </th><th align="center" rowspan="2" colspan="1">
Duration </th><th align="center" rowspan="2" colspan="1"> Dosage </th><th align="left" rowspan="2" colspan="1">
Type of tumor </th><th align="center" rowspan="2" colspan="2"> Tumor frequency (%) </th></tr><tr><th align="left" rowspan="1" colspan="1">
Species, strain </th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"> [##REF##12778218##39##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 103 w </td><td align="center" rowspan="1" colspan="1"> 0.00% </td><td align="left" rowspan="1" colspan="1"> Hepatic tumors </td><td align="center" colspan="2" rowspan="1"> 6 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0.60% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 12 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1.20% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 24 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 103 w </td><td align="center" rowspan="1" colspan="1"> 0.00% </td><td align="left" rowspan="1" colspan="1"> Hepatic tumors </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0.60% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 12 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1.20% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 26 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##3690505##41##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0.00% </td><td align="left" rowspan="1" colspan="1"> Hepatic tumors </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0.03% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 6 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0.10% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 5 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1.20% </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 30 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##8998951##42##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Oral </td><td align="center" rowspan="1" colspan="1"> 24 m </td><td align="center" rowspan="1" colspan="1"> 0 (water) </td><td align="left" rowspan="1" colspan="1"> Liver carcinoma </td><td align="center" colspan="2" rowspan="1"> 4 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 (vehicle) </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 12 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 50 mg/kg </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 6 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 150 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 6 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 500 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Oral </td><td align="center" rowspan="1" colspan="1"> 24 m </td><td align="center" rowspan="1" colspan="1"> 0 (water) </td><td align="left" rowspan="1" colspan="1"> Liver adenoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 (vehicle) </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 50 mg/kg </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 150 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 500 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Oral </td><td align="center" rowspan="1" colspan="1"> 24 m </td><td align="center" rowspan="1" colspan="1"> 0 (water) </td><td align="left" rowspan="1" colspan="1"> Liver carcinoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 (vehicle) </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 50 mg/kg </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 150 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 4 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 500 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##8998951##42##] Mouse B6C3F1 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Oral </td><td align="center" rowspan="1" colspan="1"> 18 m </td><td align="center" rowspan="1" colspan="1"> 0 (water) </td><td align="left" rowspan="1" colspan="1"> Liver carcinoma </td><td align="center" colspan="2" rowspan="1"> 8 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 (vehicle) </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 12 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 50 mg/kg </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 12 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 200 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 14 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 750 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 18 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Oral </td><td align="center" rowspan="1" colspan="1"> 18 m </td><td align="center" rowspan="1" colspan="1"> 0 (water) </td><td align="left" rowspan="1" colspan="1"> Liver adenoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 (vehicle) </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2EH 50 mg/kg </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 200 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 750 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">2</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Oral </td><td align="center" rowspan="1" colspan="1"> 18 m </td><td align="center" rowspan="1" colspan="1"> 0 (water) </td><td align="left" rowspan="1" colspan="1"> Liver carcinoma </td><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 (vehicle) </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 50 mg/kg </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 200 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 6 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2EH 750 </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##4053278##43##] Rat F344</td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular neoplastic nodule</td><td align="center" colspan="2" rowspan="1"> 4 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 14 </td></tr><tr><td align="left" rowspan="1" colspan="1">
</td><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 4 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 16 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular neoplastic nodule</td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 8 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##4053278##43##] Mouse B6C3F1 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 18 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
3000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 29 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 38 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular adenoma </td><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
3000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 23 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 20 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
3000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 14 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 34 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular adenoma </td><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
3000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##10478855##40##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 40 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular adenoma </td><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 20 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular adenoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 105 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 1 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 5 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 30 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 13 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular adenoma </td><td align="center" colspan="2" rowspan="1"> 5 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 5 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 12 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 26 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 22 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular carcinoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 18 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 7 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 105 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1"> Hepatocellular adenoma </td><td align="center" colspan="2" rowspan="1"> 0 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 6 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 2 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 3 </td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"> 10 </td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##10478855##40##] Mouse B6C3F1 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">7</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular adenoma</td><td align="center" colspan="2" rowspan="1">7</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">20</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">7</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">13</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular adenoma</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">27</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 105 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td align="center" colspan="2" rowspan="1">6</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">8</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">14</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">22</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">31</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">22</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular adenoma</td><td align="center" colspan="2" rowspan="1">6</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">17</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">20</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">22</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">27</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">5</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 105 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td align="center" colspan="2" rowspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">3</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">5</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">15</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">23</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">42</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Hepatocellular adenoma</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">3</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">6</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 1500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">14</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 6000 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">49</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">24</td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##4053278##43##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1">
0, 6000,
12000 ppm </td><td align="left" rowspan="1" colspan="1">Pituitary adenoma or carcinoma</td><td align="center" colspan="2" rowspan="1">Decrease in highest dose</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0, 6000,
12000 ppm </td><td align="left" rowspan="1" colspan="1">Pituitary adenoma or carcinoma</td><td align="center" colspan="2" rowspan="1">Decrease in lower dose</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0, 6000,
12000 ppm </td><td align="left" rowspan="1" colspan="1">Thyroid C-cell adenoma or carcinoma</td><td align="center" colspan="2" rowspan="1">Decrease in highest dose (unclear)</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0, 6000,
12000 ppm </td><td align="left" rowspan="1" colspan="1">Testis interstitial cells tumor </td><td align="center" colspan="2" rowspan="1">Decrease in highest dose</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Feed </td><td align="center" rowspan="1" colspan="1"> 2 y </td><td align="center" rowspan="1" colspan="1"> 0, 6000,
12000 ppm </td><td align="left" rowspan="1" colspan="1">Mammary gland</td><td align="center" colspan="2" rowspan="1">Decrease in highest dose</td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##10828276##36##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 78 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Interstitial cells tumor or testes</td><td align="center" colspan="2" rowspan="1">90</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">100</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">30</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 104 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Interstitial cells tumor or testes</td><td align="center" colspan="2" rowspan="1">92</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">90</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">91</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">92</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">31</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Mononuclear cell leukemia</td><td align="center" colspan="2" rowspan="1">23</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">26</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">29</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">49</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">42</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Pancreatic acinar cell adenoma</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">8</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 104 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Mononuclear cell leukemia</td><td align="center" colspan="2" rowspan="1">22</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">34</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">20</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">25</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">26</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Pancreatic acinar cell adenoma</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
100 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 2500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">3</td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##11560248##44##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Interstitial cells tumor or testes</td><td align="center" colspan="2" rowspan="1">90</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">30</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Mononuclear cell leukemia</td><td align="center" colspan="2" rowspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">10</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 105 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Interstitial cells tumor or testes</td><td align="center" colspan="2" rowspan="1">92</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1">
12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">31</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">32</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0 ppm </td><td align="left" rowspan="1" colspan="1">Mononuclear cell leukemia</td><td align="center" colspan="2" rowspan="1">23</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 12500 ppm </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">42</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> Recovery </td><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1">53</td></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##11099649##35##] Mouse B6C3F1 </td><td align="center" rowspan="1" colspan="1"> M, </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 78 w, </td><td align="center" rowspan="1" colspan="1">
0, 100,
500, 1500, 6000 ppm </td><td align="left" rowspan="1" colspan="1">No data about tumors</td><td align="center" colspan="2" rowspan="1"/></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##11560248##44##] Rat F344 </td><td align="center" rowspan="1" colspan="1"> F </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm,
12500 ppm </td><td align="left" rowspan="1" colspan="1">No data about tumors</td><td align="center" colspan="2" rowspan="1"/></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="left" rowspan="1" colspan="1"/><td align="center" colspan="2" rowspan="1"/></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##11560248##44##] Mouse B6C3F1 </td><td align="center" rowspan="1" colspan="1"> M, </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 79 w </td><td align="center" rowspan="1" colspan="1">
0 ppm,
6000 ppm, </td><td align="left" rowspan="1" colspan="1">No data about tumors</td><td align="center" colspan="2" rowspan="1"/></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> M, </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 105 w </td><td align="center" rowspan="1" colspan="1"> 0 ppm,
6000 ppm, </td><td align="left" rowspan="1" colspan="1">No data about tumors</td><td align="center" colspan="2" rowspan="1"/></tr><tr><td align="left" rowspan="1" colspan="1"> [##REF##17575397##45##] Mouse 129/Sv, PPAR<italic>α</italic>-null </td><td align="center" rowspan="1" colspan="1"> M </td><td align="center" rowspan="1" colspan="1"> Diet </td><td align="center" rowspan="1" colspan="1"> 21 m </td><td align="center" rowspan="1" colspan="1"/><td align="left" rowspan="4" colspan="1">Liver tumors (hepatocellular adenoma, hepatocellular carcinoma, cholangiocellular carcinoma)</td><td align="center" rowspan="1" colspan="1">Wild-type</td><td align="center" rowspan="1" colspan="1">PPAR<italic>α</italic>-null</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0% </td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0.01% </td><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"/><td align="center" rowspan="1" colspan="1"> 0.05% </td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">25.8</td></tr></tbody></table></table-wrap>
<graphic xlink:href="PPAR2008-759716.001"/> <graphic xlink:href="PPAR2008-759716.002"/>
[{"label": ["16"], "surname": ["Lemberger", "Desvergne", "Wahli"], "given-names": ["T", "B", "W"], "article-title": ["Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology"], "italic": ["Annual Review of Cell and Developmental Biology"], "year": ["1996"], "volume": ["12"], "fpage": ["335"], "lpage": ["363"]}, {"label": ["19"], "surname": ["Lapinskas", "Corton"], "given-names": ["PJ", "JC"], "article-title": ["Peroxisome proliferator-activated receptor "], "italic": ["\u03b1", "CIIT Activities"], "year": ["1997"], "volume": ["17"], "issue": ["1"], "fpage": ["1"], "lpage": ["8"]}, {"label": ["20"], "surname": ["Lai"], "given-names": ["DY"], "article-title": ["Rodent carcinogenicity of peroxisome proliferators and issues on human relevance"], "italic": ["Journal of Environmental Science and Health, Part C"], "year": ["2004"], "volume": ["22"], "issue": ["1"], "fpage": ["37"], "lpage": ["55"]}, {"label": ["22"], "surname": ["Gonzalez"], "given-names": ["FJ"], "article-title": ["Animal models for human risk assessment: the peroxisome proliferator-activated receptor alpha-humanized mouse"], "italic": ["Nutrition Reviews"], "year": ["2007"], "volume": ["65"], "issue": ["supplement 1"], "fpage": ["2"], "lpage": ["6"]}, {"label": ["61"], "surname": ["IARC"], "comment": ["2000, "], "ext-link": ["http://monographs.iarc.fr/ENG/Monographs/vol77/volume77.pdf"]}, {"label": ["64"], "surname": ["The Japan Society for Occupational Health"], "comment": ["2007, "], "ext-link": ["http://joh.med.uoeh-u.ac.jp/oel/index.html"]}, {"label": ["65"], "surname": ["U.S. Environmental Protection Agency"], "article-title": ["Proposed OPPTS Science Policy: PPAR"], "italic": ["\u03b1"], "comment": ["2003, "], "ext-link": ["http://www.epa.gov/scipoly/sap/meetings/2003/december9/peroxisomeproliferatorsciencepolicypaper.pdf"]}, {"label": ["66"], "surname": ["U.S. Food and Drug Administration"], "article-title": ["Preclinical and clinical safety assessment for PPAR agonist"], "comment": ["2004, "], "ext-link": ["http://www.fda.gov/cder/present/DIA2004/Elhage.ppt"]}]
PPAR Res. 2008 Aug 31; 2008:759716