Association between parental occupational exposure and childhood malignancy. A review of epidemiological studies

The question whether occupational exposure of parents to chemicals, electromagnetism and radiation causes malignant disease in their offspring has gained much interest. The findings to date, however, have been conflicting perhaps due to differences in the methods employed in these studies. A review was made on 16 case-control epidemiological studies. In 11 studies significant relation was observed between malignant tumor (leukemia, brain tumor and others) and occupational exposure to hydrocarbons, spray paint or other chemicals, ionizing radiation and electromagnetism. Conversely, no association was observed in five studies, in which different populations, different techniques, and different control groups were employed. The purpose of this paper is to examine the role of occupational exposure of the parents to chemicals and other agents in the development of malignant tumors in their offspring in relation to the employed epidemiological methodology.     

Testicular cancer in young men and parental occupational exposure

To investigate whether parental occupation, especially during the 12 month period before birth, could be responsible for elevated rates of testicular cancer in young men, we used data from a case-control study of 223 cases and 212 controls conducted in the Washington, DC area. For all histologic types of testicular cancer combined, no significant associations were found for specific occupations, nor for the broad occupational categories of professional, other white collar, or blue collar workers. However, for cases with seminomas, excess risks were seen for those with parents employed in the following occupations: mothers in health-related occupations, O.R. = 4.6 (1.1-19.1), and fathers working in automobile service stations, O.R. = 4.0 (0.6-24.5), manufacturing industries, O.R. = 2.2 (1.0-4.2), and aircraft production and maintenance, O.R. = 5.3 (0.7-24.1). Although these findings for seminoma are intriguing, they do not explain the increase of testicular cancer in young men.     

Development and evaluation of parental occupational exposure questionnaires for a childhood leukemia study

OBJECTIVES: This paper presents the results of a pilot study of job-specific modules developed for use in the study questionnaire of the Northern California Childhood Leukemia Study (i) to estimate the variability in response between people administered the same module and (ii) to estimate the number of modules required per family. METHODS: For 63 participants in the pilot study, between-person variability was assessed by comparing reported job tasks among the respondents administered the same job-specific module. Within-respondent variability was assessed by examining changes in the timing and frequency of the job tasks and product use across critical time segments from 12 months before the child's birth to 3 years of age. Parental occupational histories were reviewed to estimate the expected number of job-specific modules required per family. RESULTS: Considerable variability was identified for the tasks performed by the respondents with similar jobs and in the timing of tasks and products used across critical time windows. Parents' occupational histories indicated that detailed exposure information could be obtained for 95% of the families with a maximum of two job-specific modules added to the study interview. CONCLUSIONS: The job-specific modules captured individualized exposure information for the parents of cases and controls and thus reduced the potential for nondifferential misclassification when compared with the use of a job title approach, while avoiding an exposure checklist approach. These improvements in exposure estimation may increase the statistical power for identifying any true association between parental occupational exposures and childhood leukemia.     

Validity of self-reported occupational noise exposure

In all epidemiological studies the validity of self-reported questionnaire data is an important issue as the exposure assessment based on such data is a major source of bias in the risk estimation. A validation study was conducted based on a case–control study including 94 acoustic neuroma cases and 191 matched controls from the German Interphone Study to investigate the level of agreement between self-reported occupational noise exposure and a job-exposure-matrix (JEM) on noise exposure derived from a lifetime occupation calendar. The JEM was generated based on measurement data collected in the literature for various occupations. Level of agreement was investigated by using sensitivity, specificity, kappa coefficient and the Youden-Index. The receiver operating characteristics curve yielded an optimal cut point of 80 decibel(Acoustic) (dB(A)) to dichotomize noise exposure, displaying a moderate agreement between self-reported exposure and the JEM-based exposure (kappa of 0.53) that was slightly higher for cases than controls (kappas of 0.62 and 0.48). The agreement was only slightly lower if the longest held job or the last held job were used instead of the loudest job of the lifetime job history. The cut point of 80 dB(A) corresponds with regulations for workers safety with a recommendation to wear noise protection. The good levels of agreement between self-reported high occupational noise exposure compared with JEM-data, together with no substantial differences between cases and controls, suggest that self-reported data on occupational noise exposure is a valid exposure metric. Noise exposure appears to be appropriate if only exposure information on the last or the longest held job is available.

Bias in occupational epidemiology studies

The design of occupational epidemiology studies should be based on the need to minimise random and systematic error. The latter is the focus of this paper, and includes selection bias, information bias and confounding. Selection bias can be minimised by obtaining a high response rate (and by appropriate selection of the control group in a case-control study). In general, it is important to ensure that information bias is minimised and is also non-differential (for example, that the misclassification of exposure is not related to disease status) by collecting data in a standardised manner. A major concern in occupational epidemiology studies usually relates to confounding, because exposure has not been randomly allocated, and the groups under study may therefore have different baseline disease risks. For each of these types of bias, the goal should be to avoid the bias by appropriate study design and/or appropriate control in the analysis. However, it is also important to attempt to assess the likely direction and strength of biases that cannot be avoided or controlled.     

Parental occupational exposure to pesticides and childhood brain cancer

The authors examined the risk of childhood brain cancer in relation to parental exposure to classes of pesticides among 154 children diagnosed with astrocytoma and 158 children diagnosed with primitive neuroectodermal tumors (PNET) in the United States and Canada between 1986 and 1989. Controls were selected by random digit dialing and were individually matched to cases by race, age, and geographic area. Each job in the fathers' work history and the usual occupation of mothers were assigned a probability, intensity, and frequency of exposure to insecticides, herbicides, and agricultural and nonagricultural fungicides. Elevated risks of astrocytoma were found for paternal exposure (ever vs. never) to all four classes of pesticides (odds ratio (OR) = 1.4-1.6). An increased risk of PNET was observed for only herbicides (OR = 1.5). For mothers, odds ratios for astrocytoma were elevated for insecticides, herbicides, and nonagricultural fungicides (OR = 1.3-1.6) but not agricultural fungicides (OR = 1.0). No indication was found of an increased risk for PNET. There was little indication for an association with cumulative and average parental exposure. Most risk estimates were around unity, and exposure-response patterns were absent. Overall, it seems unlikely that parental exposure to pesticides plays an important role in the etiology of childhood brain cancer.     

Relations between asbestos exposure and lung cancer SMRs in occupational cohort studies

It has long been accepted that excessive exposure to asbestos may produce lung cancer but not that there is a consistent "biological gradient." This can only be evaluated reliably in studies where, for every individual, exposure has been measured in terms of both duration and intensity. Even now, there are only at most eight such cohort studies of asbestos workers, while femoral methods of analysis have been available only recently. These methods, applied in these studies, yield good evidence that the "exposure-response" relation between accumulated exposure to asbestos and standardised mortality ratios (SMRs) for lung cancer may be taken as linear, but that at zero exposure the lung cancer SMR is not always unity--not surprising, because of well known difficulties with the choice of reference population and selection problems. This leads to a concept of "relative slopes" that take account of the background mortality in the cohort and make what appears to be the best use of the available data. Other approaches to the same data, and indeed to all cohort data known, are also considered. Each study is examined as closely as is possible in a short review, and the concepts of linearity and relative slopes appear justified. The relative slopes (b/a) in the line SMR = a[1 + (b/a) . (exposure)] vary much more widely than can be accounted for by differences in epidemiological methodology; as discussed elsewhere, reasons for the variation seem to lie rather in type and dimensions of asbestos fibre, industrial process, etc. Slopes in the line SMR = 1 + b1 . (exposure) vary about twice as much as do the relative slopes.     

Maternal exposure to occupational solvents and childhood leukemia

Many organic solvents are considered probable carcinogens. We carried out a population-based case-control study including 790 incident cases of childhood acute lymphoblastic leukemia and as many healthy controls, matched on age and sex. Maternal occupational exposure to solvents before and during pregnancy was estimated using the expert method, which involves chemists coding each individual's job for specific contaminants. Home exposure to solvents was also evaluated. The frequency of exposure to specific agents or mixtures was generally low. Results were generally similar for the period ranging from 2 years before pregnancy up to birth and for the pregnancy period alone. For the former period, the odds ratio (OR), adjusted for maternal age and sex, for any exposure to all solvents together was 1.11 [95% confidence interval (CI), 0.88-1.40]. Increased risks were observed for specific exposures, such as to 1,1,1-trichloroethane (OR = 7.55; 95% CI, 0.92-61.97), toluene (OR = 1.88; 95% CI, 1.01-3.47), and mineral spirits (OR = 1.82; 95% CI, 1.05-3.14). There were stronger indications of moderately increased risks associated with exposure to alkanes (C5-C17; OR = 1.78; 95% CI, 1.11-2.86) and mononuclear aromatic hydrocarbons (OR = 1.64; 95% CI, 1.12-2.41). Risk did not increase with increasing exposure, except for alkanes, where a significant trend (p = 0.04) was observed. Home exposure was not associated with increased risk. Using an elaborate exposure coding method, this study shows that maternal exposure to solvents in the workplace does not seem to play a major role in childhood leukemia.     

Paternal occupational exposures and childhood cancer

The objective of the study described here was to test the hypothesis that paternal occupational exposure near conception increases the risk of cancer in the offspring. We conducted a cohort study based on a population of 235,635 children born shortly after two different censuses in Sweden. The children were followed from birth to 14 years, and cases of cancer were identified in the Swedish Cancer Registry. Occupational hygienists assessed the probability of exposure to different agents in each combination of the father's industry and occupation as reported in the censuses. We also analyzed individual job titles. We compared the cancer incidence among children of exposed fathers to that among children of unexposed fathers using Cox proportional hazards modeling. The main findings were an increased risk of nervous system tumors related to paternal occupational exposure to pesticides [relative risk (RR) = 2.36; 95% confidence interval (CI), 1.27-4.39] and work as a painter (RR = 3.65; 95% CI, 1.71-7.80), and an increased risk of leukemia related to wood work by fathers (RR = 2.18; 95% CI, 1.26-3.78). We found no associations between childhood leukemia and paternal exposure to pesticides or paint. Our results support previous findings of an increased risk of childhood brain tumors and leukemia associated with certain paternal occupational exposures. Some findings in previous studies were not confirmed in this study.     

Relations between asbestos exposure and lung cancer SMRs in occupational cohort studies.

It has long been accepted that excessive exposure to asbestos may produce lung cancer but not that there is a consistent "biological gradient." This can only be evaluated reliably in studies where, for every individual, exposure has been measured in terms of both duration and intensity. Even now, there are only at most eight such cohort studies of asbestos workers, while femoral methods of analysis have been available only recently. These methods, applied in these studies, yield good evidence that the "exposure-response" relation between accumulated exposure to asbestos and standardised mortality ratios (SMRs) for lung cancer may be taken as linear, but that at zero exposure the lung cancer SMR is not always unity--not surprising, because of well known difficulties with the choice of reference population and selection problems. This leads to a concept of "relative slopes" that take account of the background mortality in the cohort and make what appears to be the best use of the available data. Other approaches to the same data, and indeed to all cohort data known, are also considered. Each study is examined as closely as is possible in a short review, and the concepts of linearity and relative slopes appear justified. The relative slopes (b/a) in the line SMR = a[1 + (b/a) . (exposure)] vary much more widely than can be accounted for by differences in epidemiological methodology; as discussed elsewhere, reasons for the variation seem to lie rather in type and dimensions of asbestos fibre, industrial process, etc. Slopes in the line SMR = 1 + b1 . (exposure) vary about twice as much as do the relative slopes.     

Do quantitative exposure assessments improve risk estimates in occupational studies of cancer?

Quantitative assessment of exposure intensity is a difficult process, particularly for jobs held long ago. Despite difficulties, the use of this approach is growing in occupational epidemiology because it is hoped that the estimates will more closely approximate delivered dose than more traditional measures such as duration of exposure. If this assumption is correct, development and use of quantitative exposure estimates should reduce nondifferential exposure misclassification, sharpen exposure-response gradients, and enhance interpretation of study results. In this report, we used two methods to assess the value of quantitative exposure assessments in cancer epidemiology. In one, we surveyed the literature for investigations on occupational cancer that included assessments of both duration and intensity of exposure. The results of this survey indicated that exposure measures based on some measure of intensity of exposure yielded monotonically increasing exposure-response gradients and larger relative risks more often than those based on duration of exposure. Duration of exposure, however, occasionally provided the larger relative risks. In another approach, we found that different measures of exposure to formaldehyde classified subjects quite differently. For example, duration of exposure was unrelated to average exposure and was only weakly associated with exposure intensity or peak exposure. Because different measures of exposure may classify subjects quite differently and because quantitative estimates usually, but not always, yield larger relative risks and sharper exposure-response gradients than other measures of exposure, we believe that the prudent approach in epidemiologic investigations would be to develop quantitative estimates of exposure and to conduct analyses using several different measures of exposure, or combinations such as duration by intensity. Multiple comparisons would, however, increase chance findings. The value of such an approach is twofold. When a true association exists, use of several different measures decreases the chances of an unfortunate selection of an exposure measure that is poorly related to delivered dose, which would tend to produce negative results, and increases the chances of uncovering sharper exposure-response gradients. Use of several exposure measures in investigations that fail to exhibit an association between exposure and disease would be of value because such an approach would provide greater confidence that negative findings were not simply due to exposure misclassification.     

Parental occupational exposure to pesticides and childhood germ-cell tumors

In a recently completed US case-control study (Children's Oncology Group, 1993-2001) with 253 cases and 394 controls, the authors investigated the association between parental occupational exposure to pesticides and risk of childhood germ-cell tumors. Information on occupational pesticide exposure was collected using job-specific module questionnaires and assessed by an experienced industrial hygienist. Odds ratios for childhood germ-cell tumors associated with maternal exposures before pregnancy, during pregnancy, and after the birth of the index child were 1.0 (95% confidence interval (CI): 0.8, 1.4), 1.1 (95% CI: 0.7, 1.6), and 1.3 (95% CI: 0.9, 1.8), respectively. Paternal exposures before pregnancy, during pregnancy, and after the birth of the index child were not related to germ-cell tumors (odds ratios (ORs) were 0.9 (95% CI: 0.7, 1.2), 0.8 (95% CI: 0.5, 1.2), and 0.8 (95% CI: 0.5, 1.3), respectively). When both parents had ever been occupationally exposed to pesticides before the index pregnancy, the odds ratio was 0.8 (95% CI: 0.4, 1.3). Subgroup analyses showed a positive association between maternal exposure to herbicides during the postnatal period and risk of germ-cell tumors in girls (OR = 2.3, 95% CI: 1.0, 5.2) and an inverse association between paternal exposure to pesticides during the index pregnancy and germ-cell tumors in boys (OR = 0.2, 95% CI: 0.1, 1.0). This study did not provide strong evidence supporting a relation between parental pesticide exposure in the workplace and risk of germ-cell tumors among offspring.     

Use of exposure data in occupational reproductive studies

Accurately characterizing worker exposure presents some unique problems in occupational reproductive studies. The latency period between exposure and the adverse event may be relatively brief - days, weeks, or months. Inaccurately identifying the specific exposure period which initiated the adverse event may then contribute to sizeable misclassification errors. This paper discusses different types of exposure models that can be used to help reduce misclassification and delineate the exposure-effect relationships more accurately. The advantages and disadvantages of exposure data sources are also discussed.     

Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality

OBJECTIVE: A meta-analysis was made of studies addressing occupational exposure to vinyl chloride in relation to cancer mortality. METHODS: Two recently updated multicenter cohort studies and six smaller studies were identified. For selected neoplasms, standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were abstracted (or calculated from raw data). In cases of lack of heterogeneity (P-value > or = 0.01), meta-analyses were conducted using a random-effects model. RESULTS: With SMR values ranging from 1.63 to 57.1, all six studies for which these ratios could be obtained suggested an increased risk of liver cancer. For four of these studies, excesses persisted when known cases of angiosarcoma of the liver (ASL) were excluded. The meta-SMR for liver cancers other than ASL (based on the 2 large cohorts) was 1.35 (95% CI 1.04-1.77). The meta-SMR for lung cancer was 0.90 (95% CI 0.77-1.00, based on 5 studies), although higher SMR values were reported in early studies. The meta-SMR for brain cancer, based on 5 studies, was 1.26 (95% CI 0.98-1.62). For soft tissue sarcomas, the meta-SMR based on 4 studies was 2.52 (95% CI 1.56-4.07). The meta-SMR for lymphatic and hematopoietic neoplasms in the 2 large studies was 0.90 (95% CI 0.75-1.01), although 3 of the smaller studies reported significant excesses. CONCLUSIONS: Apart from the known risk of ASL, workers exposed to vinyl chloride may experience an increased risk of hepatocellular carcinoma and soft-tissue sarcoma; however, these results may have been influenced by the underdiagnosis of true ASL. Increased mortality from lung and brain cancers and from lymphatic and hematopoietic neoplasms cannot be excluded; mortality from other neoplasms does not appear to be increased.     

Agreement between company-recorded and self-reported estimates of duration and frequency of occupational fumigant exposure

Investigators must often rely on self-reported work history information collected with questionnaires. However, little is known about the agreement between self-reported estimates of exposure and records kept by companies. As part of a cross-sectional medical study of structural fumigation workers, self-reported work history information was collected on both duration and frequency of exposure using an interviewer-administered questionnaire. All company records available on these workers were also collected. Only 15 of 81 structural fumigation companies identified by study participants as current or past structural fumigation employers had records suitable for comparison. These 15 companies employed 32 of the workers who participated in the cross-sectional medical study. The exposure information provided by the 32 workers was compared to information obtained from company records. By examining the agreement between these two data sources, potential limitations were identified in both the self-reported and company-recorded exposure data. By recognizing these limitations in the exposure data, we identified the most appropriate exposure measures to be used in subsequent data analyses. This exercise also demonstrated the difficulties in undertaking these exposure comparisons in an industry consisting of many small, independent companies. Similar difficulties with assessing exposures may be experienced by investigators studying other service industries consisting of many small, independent companies (e.g., dry cleaning, auto repair). Am. J. Ind. Med. 32:364–368, 1997. © 1997 Wiley-Liss, Inc.     

Comparison of self-reported occupational exposure with a job exposure matrix in an international community-based study on asthma

BACKGROUND: Self-reports are frequently used to assess occupational exposures in epidemiological studies on asthma, but the validity and influence of asthma status on performance is unclear. METHODS: Data on self-reported exposure to air pollutants were obtained for 16,752 randomly selected working individuals from 40 study centers, and compared to exposures obtained by a job exposure matrix (JEM). The influence of current asthma symptoms or medication was investigated. RESULTS: Specificity of self-reports amounted to 0.83 and 0.87, and sensitivity 0.48 and 0.42 for asthmatics and non-asthmatics, respectively, when compared with the JEM. Self-reported exposure, but not exposure assessed by the JEM, was more prevalent in areas with a higher community prevalence of asthma. CONCLUSIONS: The prevalence of self-reported occupational exposures seems to depend on asthmatic health status at both the individual and the community level. Associations between self-reports and asthma are likely to be biased, especially in pooled analyses combining different areas with varying prevalence rates of asthma.     

The exposure-time-response relationship between occupational asbestos exposure and lung cancer in two German case-control studies

BACKGROUND: Numerous studies have been carried out to evaluate the association between lung cancer and occupational asbestos exposure. However, the effects of timing of exposure have not been analyzed thoroughly. METHODS: Two German case-control studies with data on occupational asbestos exposure histories have been pooled. Duration of work in potentially asbestos exposed jobs and two derived weighted exposure measures are analyzed together with time since last exposure. A spline function is used to model the effect of time since exposure. RESULTS: The odds ratios (OR) and corresponding 95% confidence intervals were 1.8 (1.2, 2.7) and 2.4 (1.7, 3.4) for subjects having worked for 3 to 7 years and 8 or more years, respectively, in a job with potential asbestos exposure compared to never-exposed. Based on an evaluation of time since last exposure, the OR decreased significantly to about one-half after more than 20 years since exposure ceased. Using a spline function, applied to workers' complete exposure histories, the effect of an increment of exposure is greatest 10-15 years after that exposure was received. CONCLUSIONS: In contrast to previous indications, the risk of lung cancer increases soon after asbestos exposure, with its maximum effect from 10 to 15 years after the exposure was received.     

Laryngeal cancer and occupational exposure to asbestos

Summary The risk of laryngeal cancer associated with occupational exposure to asbestos was evaluated by a review of published reports. In only two of 13 cohort studies was the standardized mortality ratio (SMR) significantly increased. Smoking (a risk factor for laryngeal cancer) may have been more prevalent among asbestos workers than among the comparison populations. This was not taken into account in any of the studies, and may have caused the SMRs to be overestimated. Two of eight case-control studies reported large odds ratios ( 13) for laryngeal cancer. Subsequent case-control studies did not confirm this higher risk; the odds ratios in these studies were 0.3 to 1.9. The conclusion of the review, based on data from 13 cohort and 8 case-control studies, is that neither case-control nor cohort studies have established an increased risk of laryngeal cancer for asbestos workers.     

Primary liver cancer and occupational exposure.

In a dynamic population-based case-referent study on primary liver cancer and occupational exposure, the work histories of 344 cases and 861 referents, derived from the follow-up of the whole Finnish population in 1976-1978 and 1981, were analyzed by industry, occupation, and agent. After adjustment for alcohol consumption, elevated odds ratios were found for the categories other agricultural workers (mainly milkmaids), clerical workers, persons exposed to welding fumes and those exposed to other inorganic dusts (mainly silica). One possible explanation for the excess among milkmaids was exposure to dust from cattle feed contaminated with aflatoxins. The excess among clerical workers was probably due to nonoccupational factors or chance because occupational exposure was generally rare. The excesses for welding fumes and inorganic dusts, although compatible with occupational etiology, contradict the results of many previous studies carried out among workers exposed to silica dust and welders.