3 Risk quantification in the range of observed cancer incidences
3.7 Procedure in the case of available human data
The relevance attached to epidemiological observation studies in the quantification of occupational cancer risks as compared with animal studies has already been dis-cussed in Section 1.1 and in the explanations of the data to be used as a basis (Sec-tion 1.5 (1)). For the risk term applied here see Sec(Sec-tion 1.4 (Risk figure)
The following references on the procedure require an adequate epidemiological data-base (for minimum criteria see Section 7.6 of this Guide).
(1) The selection of epidemiological studies should be based on the follow-ing procedure:
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Evidence from available studies should be identified by means of a well-structured, systematic literature search and reviewed for its quality and suitability for risk assessment. Principles established for the selection of occupational epidemiological studies for carrying out a meta-analysis should be considered here. It must be decided in each individual case whether several studies are combined to a pooled estimator for an as-sessment in a meta-analysis or whether individual studies are assessed separately to be able to specify a range of potential risk scenarios.
Literature: Blair et al., 1995; Roller et al., 2006, Chapter 5.2
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In general, analytical study designs with an individual exposure estimate are to be selected for risk assessment. Both cohort and case control studies can be used for risk assessment.
Study designs used in occupational epidemiology can be classified in the following descending order of evidence: (1) cohort study; (2) case-control study (CCS); (3) cross-sectional study (CS); (4) ecological or correlation study (see also Glossary).
Quantitative exposure data are more often available from cohort studies, whereas case-control studies generally guarantee a better consideration of confounding (for further details on the special strengths and weaknesses of study designs see Ahrens et al. 2008). When justified, in exceptional cases, e.g. in the case of a case-control
study embedded in a cohort with more specific or detailed information on exposure and/or the end point, a CCS can be more appropriate for an assessment of occupa-tional exposure limits than the underlying cohort study.
(2) The consideration of target parameters should be based on the following procedure:
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In general, preference is to be given to measures with reference to can-cer incidence over those to cancan-cer mortality unless incidence and mor-tality are regarded as identical because high lethality is involved in a specific type of cancer (as e.g. in the case of lung carcinoma).
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The information density of the strata decreases, the more finely the con-sidered end points are classified. It must thus be concon-sidered in each in-dividual case whether different end points can be combined in an appro-priate way to increase the statistical power (i.e. combination of various related tumour entities into one group) even if causal factors may differ in detail, e.g. in the case of leukaemias and lymphomas, head-neck tu-mours, etc.
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It must be decided in each individual case whether early end points such as biological markers, which are regarded as necessary precursors on the causal chain to an examined target disease, may be included in the assessment of the available studies as a surrogate parameter. It is ap-propriate to include them if evidence of an early clinical effect is to be regarded as a warning signal.
(Warning signals can justify the introduction of preventive measures.)
(3) The following procedure may be used for the calculation of the risk fig-ure:
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A point estimator for every exposure category (e.g. median and geomet-ric mean) is the preferred specification for risk derivation.
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If merely an exposure range was reported (e.g. 1-9 ppm-years), the class mean (here 5 ppm-years) can be used alternatively as a basis for the cal-culation. Concentrations specified in mg/m
3should be converted to sub-stance-specific ppm. This calculation is based on 240 working days/year and an inhaled volume of e.g. 10 m
3per working day, which is estimated to be 8 hours (the inhaled volume depends on the workload; 10 m
3refers to slight to moderate physical activity).
(See van Wijngaarden and Hertz-Picciotto, 2004 and Section 4.5 of this Guide)
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Subsequently, the cumulative concentrations specified in ppm-years must be converted to the long-term mean after 40 years.
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Depending on the database, direct measures of absolute risk (e.g.
cumu-lative risk) or – if these were not reported – measures of the recumu-lative risk
must be related to exposure. Measures such as SMR, SIR, RR or OR will
generally be available. For the calculation of the lifetime risk of the
ex-posed persons, these relative risk increases can be multiplied by an
es-timated value for the lifetime risk of the reference group, e.g. the general
population, unless the detailed life table method is used.
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The risk measure reported for the exposure range (RR/SIR, etc.) can be correlated with the cumulative exposure value in a regression analysis, which allows extrapolation into the high or low risk range and state-ments to be made about the risk per unit increase (1 ppm) of exposure.
In this way, the lifetime risk can be assessed in relation to a specific ex-posure level or an assumed occupational exex-posure limit.
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After subtraction of the risk of the non-exposed persons (e.g. general population), an estimated value of the exposure-related excess risk is obtained.
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Restrictions of the validity of the results are to be discussed.
A procedure in analogy to Roller et al., 2006 and Goldbohm et al., 2006 has therefore been suggested.
Bias, possible residual confounding and misclassification, for example, may restrict the validity of the results. Risk estimators that were adjusted for confounder effects should be used. Calculations of adjusted vs. non-adjusted risks should be compared with each other, if possible, since adjustment depends on the model and this allows for an assessment of the intensity of possible confounding.
Inconsistent or non-existing dose-response relationships can often be observed in epidemiological studies. However, the data can also be considered in cases in which the test results only suggest the existence of a cause-effect relationship. Deviations from an expected dose-response relationship and their possible causes and conse-quences for risk extrapolation are to be discussed.
It must be considered that the described procedure ignores variations of the risk among individuals due to different susceptibility. The transferability of the results to other populations must be evaluated in each individual case. Possible restrictions of transferability, e.g. if there is a healthy worker effect, must be considered. However, these considerations are of subordinate relevance against the background of assess-ing the risk of occupational exposure and establishment of limit values to improve oc-cupational safety.
If semiquantitative exposure specifications and no other epidemiological data are available, the authors of the original publications may be contacted to be able to es-tablish classification criteria for exposure levels and thus make a quantitative expo-sure assessment.
(4) Deviations from the default are possible in the following cases:
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In order to be able to check the consistency of the results under different conditions, exposure models deviating from cumulative exposure (inten-sity, duration, exposure peaks or threshold) may also be considered de-pending on the mode of action if specific estimators were documented in the assessed literature.
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