33_Smedley_Chap33.indd 671 1/2/2013 12:56:02 PM CHAPTER 33 Principles of toxicology 672 Toxicology and dose \200\223response Toxicology is the study of the adverse effects of chem icals in humans and other living organisms. It plays a fundamental role in chemical risk as sessment. Dose \200\223response relationship The dose \200\223response relationship refers to the cor relative relationship between exposure to a chemical (dose) and the effect that occurs (res ponse). Classi \201 cation of dose \200\223response Two types of dose \200\223response relationshi p exist. Graded dose \200\223response This relates to the occurrence of effects in an individual , w ith the response varying in severity according to dose. Quantal dose \200\223response This relates to the distribution of a speci \201 c response within a population . For many chemicals, the quantal dose \200\223response relationship is charac- terized by a normal frequency distribution, represented in a frequency histogram b y a bell-shaped curve. This distribution re \202 ects differences in susceptibility to che micals within a population (biological variation), indi- cating the presence of sensitive i ndividuals and resistant individuals. Dose \200\223response parameters Several parameters can be derived from the dose \200\223re sponse relationship. \200 NOAEL : the dose at which no observable adverse effects occur \200 Lowest observable adverse effect level (LOAEL) : the lowest dose at which adverse effects are observed Threshold : the dose below which the probability of an individual responding is zero LD50 : median lethal dose, a single dose of substance that can be expected to cause death in 50% of experimentally exposed animals. This value is determined in acute systemic toxicity tests and is used to indicate the relative acute toxicity of a s ubstance. Patterns of dose \200\223response \200 With essential elements and vitamins, the shape of the graded dose \200\223response relationship in an individual is U-shaped, representing adverse effec ts which occur at low doses (de \201 ciency) and at high doses (toxicity) (Fig. 33.1) With genotoxic carcinogens, the response (development of cancer) is considered not to have a threshold (i.e. there is no dose that is associated with zero risk) (Fig. 33.2). 33_Smedley_Chap33.indd 672 1/2/2013 12:56:02 PM TOXICOLOGY AND DOSE \200\223RESPONSE 673 e s n o p s e R Region of homeostasis Deficiency Toxicity Dose Fig. 33.1 Dose \200\223response relationship for an essential substance. 100 e s n o p s e R % A B NOAEL Dose Fig. 33.2 Comparison of dose \200\223response for two compounds (A) with no threshold and ( B) with threshold. 33_Smedley_Chap33.indd 673 1/2/2013 12:56:02 PM CHAPTER 33 Principles of toxicology 674 Toxicokinetics and types of toxic effect Toxicokinetics The toxicokinetics of a substance i s the quantitation and time course of four components: \200 Absorption \200 Distributio n \200 Metabolism \200 Excretion. The toxicokinetics of a substance determines its conc entration at the tar- get organ/tissue and consequently determines its toxicity. Absorption This is the process by which substances cross membranes in the body and enter th e bloodstream. Main routes of absorption are the respiratory tract (inhalation), the skin ( dermal), and the GI tract (oral). Distribution This is the translocation of substance within the body after it has been absor bed into the blood. Metabolism (or biotransformation) This is the process by which a substance, once it is abso rbed, is changed into one or more chemically different substances (metabolites). Excretion This is the process by which a substance and/or its metabolites are elimi- nated from the body. Route and rate of excretion vary according to the substance, the most common routes being: \200 Urine \200 Feces \200 Exhaled breath. Excretion of the substance (or its metabolites) may be used for biological monitoring purposes. Types of toxic effect Several terms are used to describe the toxic effects that are associa ted with exposure to a substance. Frequently used terms are de \201 ned in the following s ection. \200 Acute effects : resulting from short periods of exposure to a relatively hig h concentration/dose of chemical, e.g. irritation of eyes, skin, and respiratory tract (tol uene, arsenic), and central nervous system depression ( n -hexane) Chronic effects : caused by repeated or prolonged exposure to a relatively low concentration/dose of chemical, e.g. central nervous toxicity (toluene), can cer of respiratory tract, skin, and liver (arsenic), and peripheral neuropathy ( n -hexane) Local effects : occur at the site of \201 rst contact with a substance 33_Smedley_Chap33.indd 674 1/2/2013 12:56:02 PM TOXICOKINETICS AND TYPES OF TOXIC EFFECT 675 Systemic effects : occur only after the substance has been absorbed into the body Immediate effects : these develop soon after exposure takes place. In contrast, delayed eff ects only become apparent some time after exposure has taken place; perhaps months or years later Reversible effects : subside once exposure ceases \200 Irreversible effects remain follow ing cessation of exposure; in some cases, irreversible effects may become progressive. Speci \201 c toxic effects Carcinogenesis Carcinogenesis is a multistage process in which exposure to a substance leads to genetic damage within the cell, resulting in uncontrolled prolif- eration of cells and ultimately the occurrence of a tumor. Carcinogenic substances are generally divided into: \200 Genotoxic mechanism: those which cause cancer by direct damage to the genetic material Non-genotoxic mechanism: those which cause cancer by indirect damage to the genetic material. Mutagenesis This is a permanent change in the genetic material of a cell (DNA), involv- ing a single gene, a block of genes, or an entire chromosome, which is passed on to the next g eneration of cells. A mutation in germ cells (repro- ductive cells such as sperm and ova an d their precursors) can result in genetic damage that is passed on to offspring (heritable genetic defects). A mutation in somatic cells (non-reproductive cells) may lead to the deve l- opment of cancer. Respiratory sensitization A state of speci \201 c airway hyper-responsiveness that is indu ced in some individuals by certain substances (respiratory sensitizers or asthmagens). Immu nological or irritant mechanisms may be involved. Skin sensitization An immunologically mediated skin reaction which occurs in some individu- als as a result of skin contact with certain substances. 33_Smedley_Chap33.indd 675 1/2/2013 12:56:02 PM CHAPTER 33 Principles of toxicology 676 Assessment of toxicity and evaluation of toxicological data Assessment of toxicity EU legis lation requires that chemicals placed on the market must undergo a risk assessment to deter mine the risks to humans and the environment. An important part of the risk assessment proc ess involves determining the intrinsic harmful properties of the substance (hazard identi \201 cation) using toxicological data. Toxicological testing Toxicological data may come from animal, human, or in vitro studies, or be based on structure \200\223activity relationships (SARs). Toxicological data for new substances and, when necessary, for existing substances are obtained using standardized tes t methods which are contained in Annex V of Directive 67/548/EEC. The standardized toxicity tests are conducted in laboratory animals or using in vitro systems. \200 Existing subst ances: any substance listed in the European Inventory of Existing Commercial Chemical Subst ances (EINECS). All substances which were commercially available in EU between January 1971 and September 1981 appear in EINECS, comprising 100,204 substances. An EINECS number is as signed to each substance. New substances: any substance that became commercially available in the EU after September 1981. These substances appear in the European List of Noti \201 ed Chemical Substances (EL INCS), which is periodically updated. Each substance is assigned an ELINCS number. Toxicological data for the following endpoints are examined: \200 Acute systemic toxicity \200 Skin irritation \200 Eye irritation \200 Skin sensitization \200 Repeated dos e toxicity \200 Mutagenicity \200 Carcinogenicity \200 Reproductive toxicity. REACH legislation This legislation (see b p. 554) emphasizes that unnecessary testing on an imals should be avoided. To this end REACH promotes: \200 The use of alternative methods for assessing hazards of substances \200 The sharing of toxicological data between regist rants. Evaluation of toxicological data Toxicological data for many substances involve uncertainti es that need to be characterized for risk assessment: \200 For most substances, toxicolog ical data are based on animal studies, often using levels of exposure that are higher than would be applicable to humans 33_Smedley_Chap33.indd 676 1/2/2013 12:56:03 PM ASSESSMENT OF TOXICITY AND EVALUATION 677 The human population is more diverse than would be expected in a group of laboratory animals, and this variability needs to be taken into consideration Toxicological data may incorporate several experimental inadequacies (e.g. inappropriate ex posure route, short duration of exposure, or deviations from standardized test methods). Uncertainty or assessment factors When evaluating toxicological data, these uncertainties a re addressed by the use of uncertainty or assessment factors. The intention is that incor- porating uncertainty factors will provide some reassurance of protec- tion against the harm ful effects of chemicals when limited information is available. Classi \201 cation and labeling Classi \201 cation and labeling involves: \200 Evaluati on of the hazards of a substance (or preparation) in accordance with EU legislation Communicating the hazard via the label. Legislation In the UK, the regulations relating to classi \201 cation and labeling are cal led the Chemical (Hazards Information and Packaging for Supply) Regulations 2009, commonly known as CHIP4. These regulations implement the EU Dangerous Substances Directive and the D angerous Preparations Directive. The regulations are in the process of being replaced by EU Regulations Classi \201 cation, Labeling and Packaging of Substances and Mixtures (CLP Regulation), introduced in 2009 and to be fully implemented in June 2015 (see b p. 41, Chemical hazards). The aim of these regulations is to ensure that people who are supplied with any chemical re ceive information on its hazards and advice on how to protect themselves, others, and the e nvironment. Classi \201 cation entails evaluating toxicological data for a substance and c omparing these against speci \201 ed classi \201 cation criteria. 33_Smedley_Chap33.indd 677 1/2/2013 12:56:03 PM CHAPTER 33 Principles of toxicology 678 Occupational exposure limits OEL is a generic term for occupational air standards, used for personal monitoring, as a means of assessing whether or not workers are exposed to unaccep table levels of a substance. Purpose The main purposes of OELs are: \200 To demonstrate compliance \200 To identify individuals at risk \200 To select control measures in order to minimize health risks \200 To enable enforcement. Factors considered in setting standards include: \200 Where the substance is used \200 Identi \201 cation of critical health effects \200 Number o f people exposed to the substance \200 Typical exposure levels \200 Control technology available \200 Cost of implementing control systems \200 Potential health bene \201 ts from exposure reduction. Workplace exposure limits \200 WELs are occupational exposure limits set for substances h azardous to health under the COSHH Regulations. HSE produces an annual list of WELs in the document EH40 A WEL is the maximum concentration of an airborne substance, averaged over a reference peri od, to which employees may be exposed by inhalation Two limit periods, referred to as the time-weighted average concentration (TWA), are used to express the WELs, i.e. the long term (8h) and the short te rm (15min) Where a substance is not assigned a WEL, this does not indicate that it is safe. Exposure t o such substances should be reduced to a level as low as reasonably practicable, taking acc ount of the toxicity of the substance In the EH40, chemicals can be assigned the notations \200\230Sk \200\231 and \200\230Sen \200\231: Sen \200\224substance capable of causing occupational asthma, including substances assigne d a risk phrase R42 (may cause sensitization by inhalation) or R42/43 (may cause sensitizat ion by inhalation and skin contact) Sk \200\224substance can be absorbed through skin, i.e. those substances for which there a re concerns that dermal absorption will lead to systemic toxicity. Deriving the WEL value: information and stages \200 Assessment of the toxicology, i.e. po tential of the substance to produce adverse health effects Identi \201 cation of NOAEL/LOAEL from the dose \200\223response relationship \200 Appli cation of uncertainty factors (safety factors) 33_Smedley_Chap33.indd 678 1/2/2013 12:56:03 PM OCCUPATIONAL EXPOSURE LIMITS 679 Estimate the highest exposure at which no adverse effects would be expected to occur in wor kers following exposure over a lifetime \200 The Advisory Committee on Toxic Substances d etermines whether the derived exposure level is currently practicable; then WEL is proposed at this level. Criteria for setting WELs from EH40 \200 The WEL value is set at a level at which no adve rse effects on human health would be expected to occur based on the known/predicted effects of the substance. However, if such a level cannot be identi \201 ed with reasonable con \201 dence, or if this level is not reasonably achievable The WEL value would be based on a level corresponding to what is considered to be good control, taking into account the severity of the likely health hazard s and the costs and ef \201 cacy of control solutions. Compliance with WELs Substances assigned a WEL fall in to two groups: \200 Substances de \201 ned as carcinogens or mutagens, or that cause occupational cancer All other hazardous substances assigned a WEL. For carcinogens and mutagens, employers must ensure that the exposure is reduced as far below the WEL as is reasonably practicable. For other substances, the employer needs to ensure that the WEL is not exceeded. Units \200 Concentration of airborne particles (dusts, fumes) is expressed in milligrams per cubic meter (mg/m 3 ) In EH40, limits for dusts are usually expressed as the inhalable or respirable fraction Limits for \201 bres are expressed as \201 bres per milliliter of air ( \201 bres/mL) \200 Volatile organic substances are expressed in both parts per million by volume (ppm) and milligrams per cubic meter (mg/m 3 ). Airborne concentration can be converted from ppm to mg/m 3 (or vise versa) using the follow ing equation: WEL (mg/m 3 ) = WEL (ppm) (cid:7) MW/24.05526 Where MW is the molecular weight of the substance and 24.05526 is the molar volume of an id eal gas at 20 C and 1atm pressure (101325 Pa, 760mmHg). 33_Smedley_Chap33.indd 679 1/2/2013 12:56:03 PM This page intentionally left blank Section 8 Epidemiology in occupational health 34 Epidemiology 683 34_Smedley_Chap34.indd 681 1/2/2013 12:57:22 PM This page intentionally left blank 683 Chapter 34 Epidemiology Measures of disease occurrence 684 Measures of association 686 Statistical inference 688 In terpretation of associations 690 Routine health statistics 692 Planning epidemiological res earch 694 Investigation of disease clusters 696 Cross-sectional surveys 698 Cohort studies 700 Case-control studies 702 Experimental studies 704 34_Smedley_Chap34.indd 683 1/2/2013 12:57:22 PM CHAPTER 34 Epidemiology 684 Measures of disease occurrence Epidemiology is concerned with the distribution and determin ants of ill- ness and disease in human populations. Various measures are used to quantify t he rates at which disorders occur in de \201 ned groups of people. These measures may rela te to a population in its entirety (crude rates), or they may be speci \201 c to de \201 ned subgroups (e.g. sex- and age-speci \201 c rates). Case de \201 nition De \201 ning a case of disease may be relatively straightforward. For exam- ple, it is usually not too dif \201 cult to decide whether or not someone has recen tly incurred a hip fracture. For some disorders, however, the dis- tinction between normali ty and abnormality may be less clear \200\223cut (e.g. hypertension, diabetes). In these ci rcumstances, case de \201 nitions should be explicit, even if somewhat arbitrary. Otherwis e, measured rates of disease cannot be meaningfully interpreted. Incidence The incidence of a disease is the rate at which new cases occur in a popu- lation over time. It is the measure of most relevance to studies of disease causation. Mortality Mortality (death) rates refer to the incidence of death from a disease. For disea ses in which a large proportion of cases are rapidly fatal (e.g. mes- othelioma), mortality serves as a good proxy for incidence. Prevalence The prevalence of a disease is the proportion of a population who are cases at a de \201 ned point in time (point prevalence) or during a de \201 ned period (period prev alence). For example, the point prevalence of rheu- matoid arthritis in a population at the time of a survey might be 1%, and the one-month prevalence of low back pain 20%. The preva lence of a disease depends upon its incidence and also on the time for which people remain cases before recovery or death. Prevalence rates may be relevant to the planning of health services. In addition, they are sometimes used as a proxy for incidence in studies of disea se causation. However, \201 ndings must be interpreted with caution, since associations w ith prevalent disease could re \202 ect effects on recovery or fatality as well as on inci dence. Proportional rates Calculation of incidence, mortality, and prevalence rates requires that the population under study be enumerated. Sometimes this is not pos- sible, but the occurre nce of a disease can be related to an indirect index of population size. For example, the p roportions of deaths attributed to brain cancer might be compared between two populations. Here the total number of deaths in each population serves as an indirect index of its size. Care is needed, however, in the interpretation of proportional rates. A high proportion of deaths from brain cancer could indicate high mortality 34_Smedley_Chap34.indd 684 1/2/2013 12:57:22 PM MEASURES OF DISEASE OCCURRENCE 685 from the disease, but it could also re \202 ect an unusually low overall death rate in the population under study. Standardized rates Rates of most diseases vary importantly with sex and age, but compar- in g multiple sex- and age-speci \201 c rates between two populations may be unduly cumbersom e. Standardization is a method of summarizing disease occurrence in a population that takes account of its sex and age distribu- tion, and thereby allows more meaningful comparison w ith other popula- tions. It can be applied to incidence, mortality, prevalence or proportio nal rates. Two methods of standardization are widely used. Direct standardization Directly standardized rates are simply a weighted average of sex- an d age- speci \201 c rates. The weighting factors being de \201 ned by the sex and age dis tribution of a standard population (e.g. the national population). Indirect standardization Indirect standardization compares the number of cases of disease i n a study population with the number that would have been expected had the study population experienced the same sex- and age-speci \201 c rates as a speci \201 ed standard populat ion (e.g. the national population). The compari- son is summarized by the ratio of observed to expected cases (sometimes expressed as a percentage). A standardized mortality ratio (S MR) is an example of such a ratio. 34_Smedley_Chap34.indd 685 1/2/2013 12:57:22 PM CHAPTER 34 Epidemiology 686 Measures of association Much of epidemiology is concerned with comparing the occurrence of disease between groups of people according to their exposure to \200\230risk factors \200 \230. A risk factor is a characteristic that is associated with an increase or reduction in the risk (rate) of a disease. The association may be directly causal (e.g. asbestos causes lung cancer) or indirect because the risk factor is a marker for a cause (e.g. yellow stai ned \201 ngers are a risk factor for lung cancer because they are a marker for smoking). Various measures are used to summarize the association between risk factors and disease. Th ey are de \201 ned here in the context of a risk factor that is classed either as present or absent. However, the de \201 nitions can readily be extended to associations with diffe rent levels of a risk factor. Attributable (excess) risk Attributable risk is the difference in risk between people with and without exposure to a risk factor. It is the measure of association that is most releva nt to decisions in risk management for individuals. For example, in deciding whether the ri sk of cancer from a speci \201 ed occupational expo- sure to ionizing radiation is accepta ble, we need to know the absolute increase in cancer incidence that is caused by the exposu re. Relative risk Relative risk is the ratio of risks in people exposed and unexposed to a risk factor. It is a commonly reported measure of association from epidemio- logical studies, a nd is related to attributable risk by the formula: AR = ( RR \200\223 1) \227 Rate unexp where AR is the attributable risk, RR the relative risk and Rate unexp the rate of disease in people who are unexposed to the risk factor. Odds ratio An odds ratio is de \201 ned as the odds of disease in a person exposed to a ri sk factor divided by the odds in someone who is unexposed. In most situations odds ratios a pproximate closely to the corresponding relative risks. However, for very common disorders (e.g. low back pain), odds ratios deviate further from the null value of one. In other word s, for posi- tive associations they are larger than the corresponding relative risk, and fo r negative associations they are smaller. Population attributable risk Population attributable risk is de \201 ned as the rate of di sease in a population minus the rate that would apply if everyone in that population were u nex- posed to the risk factor. It depends on the attributable risk in individuals and also the prevalence of exposure in the population. It is relevant to risk management for populat ions, giving an indication of the burden of disease that might be prevented by eliminating exposure to a causal factor. 34_Smedley_Chap34.indd 686 1/2/2013 12:57:22 PM MEASURES OF ASSOCIATION 687 Attributable proportion (aetiological fraction) Attributable proportion is the proportion o f all cases of disease in a popu- lation that would be prevented if the risk of disease in exposed persons were reduced to that of the unexposed. Again, its use is in risk manage- me nt for populations. The attributable fractions for different causes of a disease may sum to more than 100%. This is because where an individual is exposed to more than one cause, rem oving any one of the exposures might be suf \201 cient to prevent him getting the disease. 34_Smedley_Chap34.indd 687 1/2/2013 12:57:22 PM CHAPTER 34 Epidemiology 688 Statistical inference Populations and samples Most epidemiological studies use observations in a sample of people to draw conclusions, but a wider population from which the sample de rived. For example, the odds ratio for welders in a case-control study of pneu- monia might be taken as an estimate of the odds ratio in welders more generally. A sample statistic (t he odds ratio in the sample of people who participated in the case-control study) is used t o estimate a population parameter (the odds ratio in the population of welders more general ly). One of the limitations on this extrapolation is that samples may be unrepresentative of the ir parent populations simply by chance, especially if the sample is small in size. Statisti cal inference is the process by which uncertainties from chance variation between samples a re taken into account when drawing conclusions about populations. Two methods are commonly used \200\224hypothesis testing and estimation with con \201 dence intervals. Hypothesis testing Hypothesis testing starts with an assumption ( \200\230null hypothesis \200\230) about the population for which conclusions are to be drawn. A calculation is then made of the probability that the \201 ndings in a sample of the size studied would devia te from those expected under the null hypothesis as much as was observed. If this probabili ty ( \200\230 p -value \200\230) is suf \201 ciently low (i.e. the observed \201 ndings are suf \201 ciently unlikely under the null hypothesis), the \201 ndings are deemed to be \200\230statistically signi \201 cant \200\230, and the null hypothesis may be rejecte d. When reporting hypothesis tests, it is more informative to report the level of their statis tical signi \201 cance (i.e. the magnitude of the p-value) than simply that the p -value i s below some speci \201 ed threshold for signi \201 cance (e.g. p < 0.05). Statistical tests Statistical tests such as the chi squared ( \207 2 ) and t -tests, are a mathematical means of calculating p-values. The appropriate test varies according to the s tudy design and the nature of the data collected. One- and two-tailed tests of signi \201 cance A two-tailed p-value is the probability of d eviation from the null hypothe- sis in either direction to the extent that was observed in the study sample. For example, if the null hypothesis were of no association between expo- sure and disease, a two-tailed p-value would be the probability of \201 nding an associat ion, positive or negative, at least as strong as that observed, simply by chance. A one-tai led p -value relates to deviations from the null hypothesis in only one direction. Unless o therwise stated, quoted p-values are normally two-tailed. 34_Smedley_Chap34.indd 688 1/2/2013 12:57:22 PM STATISTICAL INFERENCE 689 Con \201 dence intervals A con \201 dence interval is a range within which a population p arameter might normally be expected to lie, assuming that the \201 ndings from a study sa mple are unbiased. Usually 95% con \201 dence intervals are quoted. The mathematical deriv ation of a 95% con \201 dence interval is speci \201 ed in such a way that, on average, ( and in the absence of bias) 95% of intervals so calculated will include the true value for the population parameter. Con \201 dence intervals are more informative than p -values, and are gener- ally the pref erred method of statistical inference in occupational health studies. 34_Smedley_Chap34.indd 689 1/2/2013 12:57:23 PM CHAPTER 34 Epidemiology 690 Interpretation of associations Epidemiological studies addressing the relationship between an exposure and disease may differ markedly in their \201 ndings. There are several pos- sible reasons for this, all of which should be considered when interpreting observed associ ations. Nature and extent of exposure If an agent or circumstance causes disease, risk may vary acc ording to the nature, intensity, and duration of exposure. Case mix The strength of an association may vary according to the mix of disease within a s peci \201 ed case de \201 nition. For example, the risk of leukemia from occupational exp osure to ionizing radiation will be higher if the case group comprises predominantly acute myeloblastic leukemia than if it is made up largely of chronic lymphatic leukemia. Bias Bias is a systematic tendency to underestimate or overestimate a param- eter of intere st because of a de \201 ciency in the design or execution of a study. There are many poten tial sources of bias, but broadly they arise because the study sample is systematically unr epresentative of the popula- tion about which conclusions are to be drawn (e.g. because of inappropri- ate selection criteria or incomplete participation of selected subjects), or fr om inaccurate information about participants. Because of the practical and ethical constraints on research in humans, bias is inevitable in epidemiological studies. The aim should be to minimize its occurrence and then allow for its potential impact when interpreting results. Chance Even if there is no systematic bias in the selection of a study sample, it may be un representative simply by chance. Gauging the potential impact of chance variation between s amples entails techniques of statistical infer- ence (con \201 dence intervals or hypothes is testing). In addition consideration should be given to what is known from other studies (including relevant non-epidemiological research). If an association is biologically implau sible or incompatible with a large body of prior research, it may be reasonable to attribut e it to chance even if it is highly signi \201 cant statistically. Confounding Confounding occurs when a risk factor under study is statistically associ- ated with another exposure or characteristic ( \200\230confounding factor \200\230) that indepe ndently determines the risk of disease. It can lead to spurious asso- ciations in the absen ce of direct causation, or cause true causal associa- tions to be under- or over-estimated. For example, lorry drivers might have an unusually high incidence of lung cancer, not beca use lorry driving causes the disease, but because they tend to smoke more than the aver- ag e. Here, smoking would be the confounding factor. 34_Smedley_Chap34.indd 690 1/2/2013 12:57:23 PM INTERPRETATION OF ASSOCIATIONS 691 Effect modi \201 cation Effect modi \201 cation occurs when the relative risk associated with a risk factor varies according to the presence or level of another characteristic or e xposure (an effect modi \201 er). For example, the relative risk of skin cancer from occup ational exposure to sunlight might vary according to skin color. 34_Smedley_Chap34.indd 691 1/2/2013 12:57:23 PM CHAPTER 34 Epidemiology 692 Routine health statistics Purpose Routinely collected health statistics are used for severa l purposes in occu- pational health: \200 Monitoring the impact of known occupational haz ards and the effectiveness of control measures As an alert to previously unrecognized hazards \200 As a background against which to asse ss the occurrence of disease in occupational groups (e.g. in cohort studies or in the inves tigation of occupational clusters of disease). Reporting schemes and registers of occupational disease Reporting schemes are used to colle ct and register information about cases of de \201 nite or probable work-related illness. Applicable to health outcomes that can be linked to occupation with reasonable con \201 de nce in the individual case. Attribution to work may be made in two ways: \200 On the timi ng and other clinical features of the illness: e.g. acute injuries and poisoning may be lin ked to work through their temporal relation to an exposure incident, and occupational asthm a may be diagnosed through the demonstration of sensitization to an agent encountered only at work From knowledge that the individual has been exposed to an agent or circumstance that carrie s a high relative risk of the health outcome. Sources in the UK Various sources of routine health statistics may be useful to occupationa l health professionals practicing in the UK: \200 Reporting schemes for occupational inju ries and diseases: these include data reported to the Health and Safety Executive under RID DOR; and various voluntary reporting schemes co-ordinated by the Center for Occupational an d Environmental Health at the University of Manchester, as part of The Health and Occupatio n Reporting Network Periodic surveys of health and work conducted by the Health and Safety Executive, including the Labor Force Survey and Workplace Health and Safety Survey ( WHASS) Statistics of social security compensation for occupational injuries and prescribed industrial diseases Statistics of mortality and cancer incidence by occupation \200\224these are published peri odically by the Of \201 ce for National Statistics (ONS) and in the past were produced by its predecessor, the Of \201 ce of Population Censuses and Surveys (OPCS) General statistics of mortality and cancer incidence: again published by ONS, these may pro vide useful background data against which to evaluate patterns of disease observed in occup ational populations \200 Hospital Episode Statistics: published by ONS, these relate to h ospital admissions by cause and procedure. They do not include information on occupation, b ut include useful data on, for example, admissions for accidental pesticide poisoning. 34_Smedley_Chap34.indd 692 1/2/2013 12:57:23 PM ROUTINE HEALTH STATISTICS 693 1 All of the statistical sources listed have their individual strengths and limitations whi ch must be taken into account when they are used. Voluntary reporting schemes within The Health and Occupation Reporting Network (THOR) \200 Occupational Physicians Reporting Activity (OPRA) \200 SWORD \200 EPI-DERM Occupation al Skin Surveillance \200 Musculoskeletal Occupational Surveillance Scheme (MOSS) \200 Surveillance of Occupational Stress and Mental Illness (SOSMI) \200 Surveillance of Infec tious Diseases at Work (SIDAW) \200 Occupational Surveillance Scheme for Audiological Phy sicians (OSSA) Occupational Surveillance of Otorhinolaryngological Disease (THOR-ENT). Further information University of Manchester. Available at: M http://www.medicine.mancheste r.ac.uk/oeh/research/ thor/schemes/ UK National Statistics (2012). Available at: M http://www.statistics.gov.uk DWP. Statistics . Available at: M http://statistics.dwp.gov.uk/asd/index.php?page=iidb HSE Workplace healt h and safety survey (WHASS) program . Available at: M http://www.hse.gov. uk/statistics/publications/whass.htm HSE Self-reported work-related illness (SWI) and workplace injuries (LFS ). Available at: M http://www. hse.gov.uk/statistics/publications/swi.htm 34_Smedley_Chap34.indd 693 1/2/2013 12:57:23 PM CHAPTER 34 Epidemiology 694 Planning epidemiological research Unlike many other types of occupational health research, epidemiologi- cal investigations often do not require expensive equipment or facilities. Ho wever, even the simplest studies must be carefully planned and rigor- ously conducted. The starting point for any investigation is one or more study question(s). These should be both worthwhile and answerable. In other words, depend- ing on what is found, the informati on generated by the study should have the potential to affect how things are done in the fu ture. Protocols A protocol is essential for any epidemiological study. It is used in seeking ethi cal approval, permissions, and funding; as a guide to data collection and analysis; and as a reference when preparing reports of the study \201 ndings. The original study protocol, together with a note of any deviations that occurred as the study progressed, should be re tained so that they are available if required for the purposes of audit and governance. If the investigator is inexperienced in epidemiological research, or lacks relevant experti se (particularly in statistics), help should be sought in pre- paring protocols. The main e lements of a protocol are: \200 Background: this sets up the study question(s), summarizi ng relevant information from earlier research, the current gaps in knowledge, and why it is important t o address these gaps. It may also describe new technical advances that allow the gaps in kn owledge to be addressed in a way that was not previously possible Study question(s): these should be explicitly stated \200 Methods: this section should de scribe how the study questions will be addressed. It should include details of which subjec ts will be eligible for study, and how they will be recruited; what data will be collected about participants, and how these data will be analyzed to answer the study question(s). It may also be relevant to include information about the validity of methods for data collect ion Plans for publication \200 Statistical power: this gives an indication of con \201 dence that the study sample will not be unrepresentative simply by chance Ethical considerations: are there ethical issues associated with the research, and if so, how will they be addressed? Permissions and agreements (if relevant) \200 Funding (if relevant). 34_Smedley_Chap34.indd 694 1/2/2013 12:57:23 PM PLANNING EPIDEMIOLOGICAL RESEARCH 695 Ethical review Most epidemiological studies require formal review by a properly con- stitut ed research ethics committee (where there is doubt advice can be sought from the chair of t he committee to which the study would be referred). The relevant committee will depend on w ho is conducting the study and from where subjects will be recruited: \200 NHS-based rese arch: via the National Research Ethics Service (NRES) 1 \200 Non-NHS research: HSE have a n ethics committee that, although primarily concerned with HSE research, will consider extr amural research in the OH \201 eld according to set criteria. 2 Ethics committees normally specify the format in which they wish to receive applications. Other approvals Research that will take place within the NHS requires permission from the N HS organization(s) that will be involved. The National Institute for Health Research provid es a coordinated system to assist researchers in obtaining the necessary approvals. 3 Questionnaires Questionnaires are often used to collect epidemiological data. They may be s elf-administered or administered at interview. Questions may be open-ended (i.e. with free text answers) or closed \200\223ended (with a \201 nite set of options from which the ans wer is chosen). Important considerations in the design of questions are their validity (wil l they provide accurately the information that is sought?), understandability, and the ease with which the answers can be analyzed. Use of previously developed questions (e.g. from w idely used questionnaires) is often an advantage. Questionnaires should collect the informa tion that is likely to be needed to address the study question(s), but unnecessary detail s hould be avoided. 1 M http://www.nres.npsa.nhs.uk/ 2 HSE Research Ethics Committee. Available at: M http://www.hse.gov.uk/research/ethics/inde x. htm 3 NICE (2012). Gaining NHS Permission for clinical research . Available at: M http://www.cr ncc.nihr. ac.uk/about_us/processes/csp 34_Smedley_Chap34.indd 695 1/2/2013 12:57:23 PM CHAPTER 34 Epidemiology 696 Investigation of disease clusters A cluster of disease is an unusually high number of cases in a de \201 ned population over a time period during which fewer than one or two cases w ould be expected. Disease clusters are not infrequent in occupational populations. Occasionally they result f rom exposure to a hazardous agent or activity in the workplace, but much more often they si mply represent a chance coincidence. Nevertheless, they can be a major cause of anxiety for both employees and managers, and require proper assessment.