Exposure-response Patterns Research Articles

Occupational Trichloroethylene Exposure and Kidney Cancer

We conducted a meta-analysis of occupational studies of trichloroethylene-exposed workers to evaluate patterns of associations by study design, exposure assessment methods, and occupational groups. Estimates of summary relative risk (RR) were calculated using inverse-variance weighting methods. Cohort studies were classified as group I or group II, depending on quality of the study design and exposure assessment procedures. We conducted sensitivity analyses to examine sources of heterogeneity. Across all studies meeting our inclusion criteria (n = 23), the summary RR was 1.42 (95% confidence interval = 1.17-1.77), with heterogeneity present (test for heterogeneity: P = 0.001). After removal of 3 outlier studies, the summary RR for the remaining studies was 1.24 (1.06-1.45 (test for heterogeneity: P = 0.616)). The summary RR for studies of workers who were identified as more likely exposed to trichloroethylene (group I studies) was 1.34 (1.06-1.68). With outlier studies removed, the group II summary RR estimates for the cohort studies was 0.88 (0.58-1.33) and for the case-control studies was 1.33 (1.02-1.73). The summary RR for studies that used biomarkers to classify exposure (n = 3) was 1.02 (0.59-1.77) and for studies of aerospace/aircraft workers (n = 7) was 1.14 (0.84-1.57). Positive associations were observed across various study groups. However, considerations of unmeasured potential confounding, lack of quantitative exposure assessment and lack of exposure-response patterns limit epidemiologic insight into the role of trichloroethylene exposure and its potential causal association with kidney cancer.

Pharmaceutical Production Workers and the Risks of Mortality From Respiratory System Cancer and Lymphatic and Hematopoietic Tissue Cancers

To evaluate further elevated mortality risks from respiratory system cancer (RSC) and lymphatic and hematopoietic tissue cancers (LHTC) in a cohort of 1466 male workers employed full-time in pharmaceutical production. We computed standardized mortality ratios, and in nested case-control studies of RSC and LHTC, evaluated mortality risks by plant exposures with adjustment for potential confounding factors. Subjects with potential plant exposure had no elevated RSC risk and a statistically significant LHTC excess. The case-control study found many RSC risks reduced with adjustment for smoking, and LHTC risks increased with increasing levels of average exposure to dimethyl-formamide. RSC mortality risks decreased, and we found limited evidence that positive confounding by smoking may explain some remaining excess risks. For LHTC, increased mortality risks and exposure-response patterns in the case-control study may indicate a possible workplace association.

Occupation and cancer – follow-up of 15 million people in five Nordic countries

Occupation and cancer – follow-up of 15 million people in five Nordic countries

The effects of recall errors and of selection bias in epidemiologic studies of mobile phone use and cancer risk

This paper examines the effects of systematic and random errors in recall and of selection bias in case-control studies of mobile phone use and cancer. These sensitivity analyses are based on Monte-Carlo computer simulations and were carried out within the INTERPHONE Study, an international collaborative case-control study in 13 countries. Recall error scenarios simulated plausible values of random and systematic, non-differential and differential recall errors in amount of mobile phone use reported by study subjects. Plausible values for the recall error were obtained from validation studies. Selection bias scenarios assumed varying selection probabilities for cases and controls, mobile phone users, and non-users. Where possible these selection probabilities were based on existing information from non-respondents in INTERPHONE. Simulations used exposure distributions based on existing INTERPHONE data and assumed varying levels of the true risk of brain cancer related to mobile phone use. Results suggest that random recall errors of plausible levels can lead to a large underestimation in the risk of brain cancer associated with mobile phone use. Random errors were found to have larger impact than plausible systematic errors. Differential errors in recall had very little additional impact in the presence of large random errors. Selection bias resulting from underselection of unexposed controls led to J-shaped exposure-response patterns, with risk apparently decreasing at low to moderate exposure levels. The present results, in conjunction with those of the validation studies conducted within the INTERPHONE study, will play an important role in the interpretation of existing and future case-control studies of mobile phone use and cancer risk, including the INTERPHONE study.

A Pooled Analysis of Bladder Cancer Case–Control Studies Evaluating Smoking in Men and Women

A recent study suggested that risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes. We pooled primary data from 14 case-control studies of bladder cancer from Europe and North America and evaluated differences in risk of smoking by gender. The pooled analysis included 8316 cases (21% women) and 17,406 controls (28% women) aged 30-79 years. Odds ratios (ORs) and 95% confidence intervals (95% CI) for smoking were adjusted for age and study. Exposure-response was evaluated in a stratified analysis by gender and by generalized additive models. The odds ratios for current smokers compared to nonsmokers were 3.9 (95% CI 3.5-4.3) for males and 3.6 (3.1-4.1) for females. In 11 out of 14 studies, ORs were slightly higher in men. ORs for current smoking were similar for men (OR = 3.4) and women (OR = 3.7) in North America, while in Europe men (OR = 5.3) had higher ORs than women (OR = 3.9). ORs increased with duration and intensity in both genders and the exposure-response patterns were remarkably similar between genders. These results do not support the hypothesis that women have a higher relative risk of smoking-related bladder cancer than men.

Evaluation of Epidemiologic and Animal Data Associating Pesticides With Parkinson???s Disease

Exposure to pesticides may be a risk factor for developing Parkinson's disease (PD). To evaluate the evidence regarding this association in the scientific literature, we examined both analytic epidemiologic studies of PD cases in which exposure to pesticides was queried directly and whole-animal studies for PD-like effects after systemic pesticide exposure. Epidemiologic studies were considered according to study quality parameters, and results were found to be mixed and without consistent exposure-response or pesticide-specific patterns. These epidemiologic studies were limited by a lack of detailed and validated pesticide exposure assessment. In animal studies, no pesticide has yet demonstrated the selective set of clinical and pathologic signs that characterize human PD, particularly at levels relevant to human populations. We conclude that the animal and epidemiologic data reviewed do not provide sufficient evidence to support a causal association between pesticide exposure and PD.

A Graphical Method to Evaluate Exposure-Response Relationships in Epidemiologic Studies Using Standardized Mortality or Morbidity Ratios

In occupational epidemiology, exposure-response analyses play an important role in the evaluation of the etiologic relevance of chemical and physical exposures. The standardized mortality or morbidity ratio (SMR) has been commonly used in occupational cohort studies. Statistical approaches to evaluate exposure-response patterns using SMRs have mostly been limited to analyses in which the exposure under investigation is categorized. Here, a graphical method for evaluating exposure-response patterns is presented based on SMR estimates across moving exposure windows. This method is demonstrated using the results of two hypothetical cohort studies. The proposed approach may be useful for graphical exploration of exposure-response trends in situations where the number of observed cases is small.

Responses of earthworms ( Lumbricus rubellus) to copper and cadmium as determined by measurement of juvenile traits in a specifically designed test system

In this study, the effects of two metals, copper and cadmium, on the growth and development of juvenile Lumbricus rubellus were measured in a toxicity test in which individuals were grown in isolation. This design had a number of advantages over traditional test systems for earthworms. Importantly, the test is specifically designed to measure two juvenile traits (survival over and length of the juvenile period) that have been shown to have a high sensitivity for determining population growth rate. The test system also maximizes replication, while allowing time-series-based monitoring of individual growth. For both metals, significant exposure-dependent effects on survival, growth, development time, and (less certainly) maturation weight were observed. Comparisons of the relative toxicity of the two metals indicated different concentration–response relationships. For copper, hormesis was found at low levels, while only at the highest soil concentration tested (10.07 μmol g −1) were (severe) toxic effects present. For cadmium, hormesis was also evident at the lowest concentration tested; however, at soil levels above this, a graded concentration-dependent toxic effect was apparent. These differences in the exposure response patterns can be (tentatively) explained in terms of the mechanisms for handling copper (an essential metal for earthworms) and cadmium (a putative nonessential element). The applicability of the test for routine measurement of chemical effects on ecologically relevant juvenile traits is also outlined and future developments are discussed.

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.

Growth response of grassland species to ozone in relation to soil moisture condition and plant strategy

Plant species typical of semi‐natural grasslands were tested for their sensitivity to long‐term ozone effects on growth under two irrigation regimes, and the relationship between ozone sensitivity, relative growth rate, and plant strategy was analysed. Individuals of 24 grasses, herbs and legumes were grown in pots and exposed for two seasons to four levels of ozone in open‐top chambers: (a) CF, charcoal‐filtered air, (b) CFAA, charcoal‐filtered air plus ozone to match ambient levels, (c) CF+, charcoal‐filtered air plus ozone added to match 1.5 times ambient levels and (d) CF++, charcoal‐filtered air with ozone added to match twice ambient levels during selected episodes of 7–13 d. During the ozone episodes, one half of the plants received reduced irrigation (dry treatment) while the rest was kept well watered (wet treatment). The effect of ozone on the relative growth rate was determined during the initial growth period during the first season. Above‐ground plant dry weight was determined three times during each season, and stubble dry weight at the end of the experiment. In most species, the effect of ozone on relative growth rate was not significant, except in Centaurea jacea and Lychnis flos‐cuculi for which a significant stimulation of relative growth rate was found. There was a significant negative relationship between percentage relative growth rate and relative growth rate measured in the CF treatment, indicating that in species growing faster in clean air relative growth rate tended to be more sensitive to ozone than in slower‐growing species. After the first re‐growth period during the first season, a significant effect of ozone on above‐ground biomass was found in five species, i.e. a decrease in Chrysanthemum leucanthemum, Trifolium pratense and T. repens, and an increase in Silene dioïca. During the second season no significant ozone effect was detected, except for an increase in stubble mass in C. leucanthemum. In 10 species, the dry treatment caused a significant decrease in biomass, but in Plantago lanceolata during the first year, and in Knautia arvensis and T. repens during the second year, an ozone×irrigation interaction was observed. Exposure–response patterns in the wet treatment varied between species. In some species growth tended to be increased in charcoal‐filtered air plus ozone to ambient levels, in others either a continuous increase or decrease in biomass was observed with increasing ozone. Trifolium repens showed the lowest AOT40 (ozone accumulated above a threshold of 40 ppb) corresponding to a 10% change in biomass. The comparison between exposure–response pattern between the wet and dry treatments revealed reduced, increased, or unchanged ozone sensitivity. The shift was related to plant strategy and not to the specific sensitivity to the dry treatment. The specific response to both ozone and dry treatment tended to be related to Grime's triangular classification of plant strategies, i.e. the C‐S‐R model. In species with a large component of C (competitor strategy), and/or R (ruderal strategy), biomass was more sensitive to both stresses, compared with species with a high component of S (stress tolerators), and ozone×drought interactions were more pronounced. The results indicate that specific relative growth rate is an important determinant for the potential sensitivity of grassland species to long‐term effects of ozone, and that reduced irrigation causes no general protection from the effects of ozone on growth.

The evolving concept of the healthy worker survivor effect.

The "healthy worker survivor effect" describes a continuing selection process such that those who remain employed tend to be healthier than those who leave employment. In an analysis of exposure-response patterns in an occupational study, the healthy worker survivor effect generally attenuates an adverse effect of exposure. In practical terms, such attenuation will be more problematic when evaluating subtle rather than strong associations. The use of an internal referent does not guarantee elimination of this effect, since by definition, it manifests within an occupational cohort. Although documented over 100 years ago, there is little consensus regarding the most appropriate method to control for the healthy worker survivor effect. Four methods have been proposed for its control: (1) restriction of the cohort to survivors of a fixed number of years of follow-up, (2) lagging the exposure to exclude recent exposure incurred by those who remained on the job, (3) adjusting for employment status as a confounder, and (4) treating the healthy worker survivor effect simultaneously as an intermediate and confounding variable by means of the G-null test or its extension, G-estimation analysis, using structurally nested failure time models. This paper reviews the concept of the healthy worker survivor effect and the four methods to control for it.

Formaldehyde exposure and respiratory cancer among woodworkers--an update.

Respiratory cancer was examined in relation to occupational formaldehyde exposure in a case-referent study (136 cases, 408 referents) nested in a woodworker cohort. Plant- and time-specific job-exposure matrices were constructed for formaldehyde exposure. Over 3 ppm-months of formaldehyde exposure was associated with an odds ratio of 1.4 [90% confidence interval (90% CI) 0.5-4.1]. The odds ratios for lung cancer were near unity, the excess risk concentrating on the upper respiratory tract. That for combined exposure to formaldehyde-phenol exposure (all respiratory cancers) was 1.6 (90% CI 0.6-4.4) but 1.0 for formaldehyde only. No consistent exposure-response patterns emerged for the level, duration, or cumulative exposure. The results are hardly more than debatable support for the hypothesis concerning formaldehyde as a carcinogen in humans, the possible risk seemingly concentrating on the upper respiratory tract rather than the lung.