Endocrine disruptors: Challenges and future directions in epidemiologic research.

Public concern about the impact of endocrine disrupting chemicals (EDCs) on both humans and the environment is growing steadily. Epidemiologic research provides key information towards our understanding of the relationship between environmental exposures like EDCs and human health outcomes. Intended for researchers in disciplines complementary to epidemiology, this paper highlights the importance and challenges of epidemiologic research in order to present the key elements pertaining to the design and interpretation of an epidemiologic study on EDCs. The conduct of observational studies on EDCs derives from a thoughtful research question, which will help determine the subsequent methodological choices surrounding the careful selection of the study population (including the comparison group), the adequate ascertainment of exposure(s) and outcome(s) of interest, and the application of methodological and statistical concepts more specific to epidemiology. The interpretation of epidemiologic results may be arduous due to the latency occurring between EDC exposure and certain outcome(s), the complexity in capturing EDC exposure(s), and traditional methodological and statistical issues that also deserve consideration (e.g., confounding, effect modification, non-monotonic responses). Moving forward, we strongly advocate for an integrative approach of expertise in the fields of epidemiology, exposure science, risk assessment and toxicology to adequately study the health risks associated with EDCs while tackling their challenges.

Inter-rater reliability of occupational exposure assessment in a case-control study of female breast cancer.

The objective of this paper was to estimate the inter-rater reliability of expert assessments of occupational exposures. An inter-rater reliability sub-study was conducted within a population-based case-control study of postmenopausal breast cancer. Detailed information on lifetime occupational histories was obtained from participants and two industrial hygienists assigned exposures to 185 jobs using a checklist of 293 agents. Experts rated exposure for each job-agent combination according to exposure status (unexposed/exposed), confidence that the exposure occurred (possible/probable/definite), intensity (low/medium/high), and frequency (% time per week). The statistical unit of observation was each job-agent assessment (185 jobs × 293 agents = 54,205 assessments per expert). Crude agreement, Gwet AC1/2 statistics, and Cohen's Kappa were used to estimate inter-rater agreement for confidence and intensity; for frequency, the intra-class correlation coefficient (ICC) was used. The majority of job-agent combinations were evaluated by the two experts to be not exposed (crude agreement >98% of decisions). The degree of agreement between the experts for the confidence of exposure status was Gwet AC1/2 = 0.99 (95% CI: 0.99-0.99), and for intensity, a Gwet AC2 = 0.99 (95% CI: 0.99-0.99). For frequency, an ICC of 0.31 (95% CI: 0.26-0.35) was found. A sub-analysis restricted to job-agent combinations for which the two experts agreed on exposure status revealed a moderate agreement for confidence of exposure (Gwet AC2 = 0.66) and high agreement for intensity (Gwet AC2 = 0.96). For frequency, the ICC was 0.52 (95% CI: 0.47-0.57). A high level of inter-rater agreement was found for identifying exposures and for coding intensity, but agreement was lower for the coding of frequency of exposure.

Estimating the burden of lung cancer in Canada attributed to occupational radon exposure using a novel exposure assessment method.

OBJECTIVE: Exposure to radon causes lung cancer. The scope and impact of exposure among Canadian workers have not been assessed. Our study estimated occupational radon exposure in Canada and its associated lung cancer burden. METHODS: Exposed workers were identified among the working population during the risk exposure period (1961-2001) using data from the Canadian Census and Labour Force Survey. Exposure levels were assigned based on 12,865 workplace radon measurements for indoor workers and assumed to be 1800 mg/m3 for underground workers. Lung cancer risks were calculated using the Biological Effects of Ionizing Radiation (BEIR) VI exposure-age-concentration model. Population attributable fractions were calculated with Levin's equation and applied to 2011 Canadian lung cancer statistics. RESULTS: Approximately 15.5 million Canadian workers were exposed to radon during the risk exposure period. 79% of exposed workers were exposed to radon levels < 50 Bq/m3 and 4.8% were exposed to levels > 150 Bq/m3. We estimated that 0.8% of lung cancers in Canada were attributable to occupational radon exposure, corresponding to approximately 188 incident lung cancers in 2011. CONCLUSIONS: The lung cancer burden associated with occupational radon exposure in Canada is small, with the greatest burden occurring among those exposed to low levels of radon.

Burden of non-melanoma skin cancer attributable to occupational sun exposure in Canada.

PURPOSE: Outdoor workers are exposed daily to solar ultraviolet radiation, an important contributor in the development of non-melanoma skin cancer. This study aimed to quantify the health burden of non-melanoma skin cancers among outdoor workers in Canada. METHODS: Solar ultraviolet radiation exposure and estimates of exposure levels were applied to employment information from Canada census data to determine the exposed population in the risk exposure period (1961-2001). Risk estimates were drawn from meta-analyses selected based on quality and relevance to the current study. Population-attributable fractions were calculated using Levin's equation and attributable cases were estimated based on incidence data reported by the Canadian Cancer Society. RESULTS: In 2011, 6.31% (4556 cases) of non-melanoma skin cancer cases were estimated to be attributable to occupational exposure to solar ultraviolet radiation. The majority of these cases occurred in men in the agriculture or construction industries. CONCLUSIONS: These estimates of the burden of non-melanoma skin cancer in Canada identify the need for further prevention efforts, particularly in agriculture and construction. Introducing workplace sun safety measures could be an important area for policy development.

Surface contamination with ten antineoplastic drugs in 83 Canadian centers.

PURPOSE: The aim of this study was to monitor environmental contamination by 10 antineoplastic drugs in Canadian oncology pharmacy and patient care areas. The secondary objective was to explore the impact of factors that may explain contamination. METHODS: Twelve standardized sites were sampled in each center (six in the pharmacy and six in patient care areas). Each sample was prepared to allow quantification of seven antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, cytarabine, gemcitabine, 5-fluorouracil, irinotecan) by UPLC-MS-MS. Docetaxel, paclitaxel and vinorelbine were also detected, but not quantified due to sensibility limitations. The impact of some factors was evaluated compared with a Kolmogorov-Smirnov test for independent samples. RESULTS: Eighty-three Canadian centers were recruited in 2017. A total of 953 surfaces were sampled, 495 in pharmacy and 458 in patient care areas. Cyclophosphamide was most often found on surfaces (36% of samples positive, 75th percentile 0.0040 ng/cm2). The arm rest (81.7% of samples positive for at least one antineoplastic drug), the front grille inside the hood (78.3%) and the floor in front of the hood (61.4%) were more frequently contaminated. Centers who prepared more antineoplastic drugs per year had higher concentration on different surfaces ( p < 0.0001). CONCLUSION: Despite growing awareness and implementation of new safe handling guidelines, healthcare centers' surfaces remain contaminated with traces of many antineoplastic drugs. The use of personal protective equipment remains indisputable. Performing an annual monitoring remains a good indicator to monitor trends over time and to compare with similar centers.

But other than mesothelioma? An estimate of the proportion of work-related cancers in Quebec.

BACKGROUND: More than 30 exposures in the workplace are proven carcinogens. In the present study, we aimed to estimate the burden of occupational cancer in Quebec so as to increase awareness among stakeholders and to prioritize research activities. METHODS: Work-attributable fractions-that is, the proportions of cancers attributable to work-as published in Finland and the United Kingdom were applied to Quebec 2002-2006 cancer incidence and mortality data to estimate the number of work-related cases for 28 cancer sites. RESULTS: Overall, 6.0% of incident cancers (men: 9.1%; women: 2.7%) and 7.6% of cancer deaths (men: 11.8%; women: 2.8%) could be attributable to work, resulting annually in an average of 2160 new cancer diagnoses and 1190 cancer deaths in Quebec. Incident cancers of the lung, prostate, skin, bladder, and (female) breast were the most numerous; cancer sites resulting in more deaths were lung, (female) breast, and pleura. During the same period, compensation statistics reported annual averages of 94.3 incident cancers and 61.9 cancer deaths, mostly involving mesothelioma (64% of compensated incident cancers) and lung cancer (30% of compensated incident cancers). CONCLUSIONS: Increased recognition of workplace cancers by all stakeholders, from workers and employers to treating physicians, will foster appropriate preventive measures for safer workplaces.

Occupational exposure to solvents and male infertility.

OBJECTIVES: To determine whether, in a case-referent study of infertility patients, cases with low motile sperm count were more likely than referents to have had exposure to organic solvents. METHODS: Occupations of men attending fertility clinics in Canada were assigned codes reflecting probable exposure to organic solvents, at four grades of intensity, using a job exposure matrix previously developed. A case referent design was used, with cases being defined as men with <12x10(6)/ml motile sperm. Information from 656 men in manual work attending a single clinic in Montreal in 1972-91 was used for the main study. A separate analysis was conducted with information for 574 men in manual work attending 10 further clinics across Canada in 1984-7. RESULTS: In the Montreal series a significant association was found between intensity of exposure to solvents and clinical findings of <12x10(6)/ml motile sperm. Odds ratios (ORs), after allowing for confounding, were 2.07 (95% confidence interval (95% CI) 1.24 to 3.44) for moderate exposure to solvents and 3.83 (95% CI 1.37 to 10.65) for high exposure. In the second series of 568 men, the effect was confirmed at high exposure to solvents (OR 2.90, 95% CI 1.01 to 8.34) but not at moderate exposure (OR 1.01, 95% CI 0.53 to 1.92). CONCLUSIONS: Exposure to organic solvents is common both at work and in recreational pursuits. The results of this study suggest that efforts should be made to identify the compounds hazardous to male fertility, and if the risk is confirmed, to regulate their use.

Exposure to organic solvents and breast cancer in women: a hypothesis.

Incidence rates for breast cancer have increased steadily over the last 25 years, particularly among postmenopausal women. Secular changes in accepted and suspected risk factors can explain only a part of this increase. Given the increasing number of women in the workforce, it is possible that increases in breast cancer incidence may be caused by occupational exposure to hazardous agents. In particular, we hypothesize that organic solvents act directly as genotoxic agents or indirectly through their metabolites. Most organic solvents are highly lipophilic and are readily absorbed and distributed throughout the body via the bloodstream. Organic solvents are biotransformed mostly in the liver and the kidneys through a series of oxidative and reductive reactions, some of them resulting in bioactivation. There are indications of P-450 enzymatic oxidative activity in the breast parenchyma, but there appears to be limited detoxification of highly reactive metabolites. The physiology of the breast may also accentuate the accumulation of chemicals: breast parenchyma is embedded in a fat depot capable of storing lipophilic xenobiotics; it is conceivable that organic solvents and their metabolites, once stored in fat tissues, migrate to the breast parenchyma and are then transferred to the mammary lobules through continuous apocrine secretions. These secretions may reside in the ductular system long enough for the solvents and their bioactivated metabolites to locally exert detrimental effects. The evidence supporting this hypothesis is that many organic solvents have been detected in breast milk, the majority of carcinomas occur in the ductular system, and some organic solvents have been shown to produce mammary gland cancer in experiments on rodents. Further toxicological and epidemiologic studies are required to test this hypothesis, to elucidate the mechanisms, and to identify specific carcinogenic organic solvents.

Physician based surveillance system for occupational respiratory diseases: the experience of PROPULSE, Québec, Canada.

OBJECTIVE: To evaluate the feasibility of implementing a physician based surveillance system of occupational respiratory diseases (PROPULSE) in Québec with regard to physician participation rate, characteristics of reported cases, and comparison with official statistics from the Workers' Compensation Board (WCB). METHODS: All chest physicians and allergists in Québec were asked to report suspected new cases of occupational respiratory diseases, on a monthly basis, between October 1992 and September 1993. For each case, personal information was collected and the physician's opinion on whether the condition was related to work was categorised as highly likely, likely, and unlikely. RESULTS: Of the 161 physicians initially approached, 68% participated. Physicians rated 48% of suspected cases as highly likely, 29% as likely, and 20% as unlikely. The most often reported diagnosis was asthma (63%), followed by diseases related to asbestos (16%). Silicosis was less frequent (5%) but it was reported for six workers under 40 of whom five were involved in sandblasting activities. The high proportion of cases of asthma probably reflects the increasing importance of this disease but may also reflect the different patterns of reporting among physicians with different expertise. The distribution of cases by diagnostic category is quite different between the PROPULSE system and that of the WCB (annual mean number of compensated cases during a four year period). Asthma and allergic alveolitis are more frequent in PROPULSE, reactive airways dysfunction syndrome are about the same in both systems, and other diseases are more frequent among compensated cases. The most frequent sensitising agents reported for asthma were the same in both systems (isocyanates, flour, and wood dust). 15% of the PROPULSE cases were not covered by the WCB, and therefore would not be found in the board's official statistics. CONCLUSIONS: A physician based reporting procedure can be implemented as part of a surveillance system to supplement data from other sources and thus provide a better understanding of the occurrence of occupational respiratory diseases.

Occupational risk factors for female breast cancer: a review.

OBJECTIVES: Although progress has been made in identifying personal risk factors and in improving treatment for female breast cancer, incidence rates continue to increase. With women now occupying a sizable fraction of the workforce, it is worth inquiring whether there are occupational risk factors for breast cancer. This is a review of occupational studies on female breast cancer. METHODS: Suitable reports and published articles with associations of female breast cancer and occupation were identified from technical reports, by searching the MEDLINE bibliographic data base, and by reviewing each paper on cancer that was published in 20 major journals during the period from about 1971-94. RESULTS: A total of 115 studies were identified; 19 studies relied exclusively on data collected for administrative purposes, and there were four incident case-control studies and 92 cohort studies. Although data for individual industries, occupations, and exposures were sparse, there was limited evidence of an association with employment in the pharmaceutical industry and among cosmetologists and beauticians. Associations were also found for chemists and occupations with possible exposure to extremely low frequency electromagnetic fields, but potential methodological weaknesses preclude drawing any definite conclusions. There was little support for increased risks among textiles workers, dry cleaning workers, and nuclear industry workers. CONCLUSIONS: Few high quality occupational studies directed specifically toward women have been carried out to allow the unambiguous identification of occupational risk factors for breast cancer. It is suggested that investigations that account for non-occupational risk factors and that assess exposure in a more detailed way be carried out. One strategy already suggested is to conduct population based, case-control studies in which subjects are interviewed about their occupational histories and exposure to chemical and physical agents which are then attributed from the job descriptions by a team of experts. These studies can then be supplemented when necessary with cohort studies of specific populations.

[Study of a cancer aggregate in a metallurgy plant: practical implications for public health]. / Etude d'un agrégat de cancer dans une enterprise de métallurgie: implications pratiques pour la santé publique.

We present the strategy used to determine whether there was an excess of laryngeal cancer at a primary metal factory in Montreal. The study period extended from 1968 to 1987. Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) were computed for different cancer sites. The number of person-years at risk was estimated (N = 10,860 person-years). This method permitted a summary evaluation of the situation. Statistically significant excesses were not observed for laryngeal cancer or any other site of cancer: SMRs and SIRs were elevated for certain cancers, particularly cancers of the larynx and cancers of the central nervous system (CNS). No association was observed with potential carcinogens in the workplace. However, all three CNS cancer cases were crane operators. Following this investigation, we recommended an industrial hygiene evaluation of the workplace.

Psychiatric disorders and occupational exposure to solvents.

Three hundred and eighty one men admitted to hospital for the first time with any psychiatric diagnosis were individually matched for age and year to patients admitted to general hospitals. An occupational history was obtained from 90% of this study group by telephone interview or mail. Exposure to solvents was assessed by three methods, individual rating of each job recorded, application of an exposure matrix based on job title, and assessment of lifetime job histories of selected case-referent pairs. A sample of individual ratings used in the analysis was compared with ratings made by five experts. The panel values tended to be lower but all six sets of ratings correlated well. There was no increased risk of psychiatric illness among subjects exposed to moderate or greater solvent concentrations for at least 10 years (odds ratio (OR) 1.0, 90% confidence interval (90% CI) 0.7-1.4, individual rating; OR 1.1, 90% CI 0.6-2.0, job title matrix; OR 0.9, 90% CI 0.5-1.7, lifetime assessments). At higher exposures the risk was increased--although not to a statistically significant degree--especially for cases with non-psychotic diagnoses (ICD-9 codes 300-316). This negative result, by all three methods of assessment of exposure, contrasted with that from a parallel investigation of cases of organic psychoses and cerebral degeneration.

Organic brain damage and occupational solvent exposure.

Three hundred and nine men with organic dementia, cerebral atrophy, or psycho-organic syndrome admitted for five nights or more to one of 18 Quebec hospitals were individually matched with patients admitted (1) with some other psychiatric diagnosis and (2) to a general hospital. Lifetime occupational histories were obtained by telephone. Occupational exposure to solvents was assessed blind to type of case by (1) individual ratings and (2) a job exposure matrix; men who worked in moderate or high solvent concentrations for at least 10 years were considered exposed. With the psychiatric referent series, an odds ratio of 1.4 (90% CI 1.0-2.0) was calculated by individual exposure ratings and 1.4 (90% CI 0.9-2.2) by job matrix. Increased risk was mainly in those with organic dementia or cerebral atrophy and an alcohol related diagnosis. The same pattern of risk was found against the general hospital referents. Adjustment for possible confounders did not alter the risk estimates appreciably. Also, lifetime job histories, compared in selected case-referent pairs, gave similar evidence of increased risk (odds ratio 2.3; 90% CI 1.0-5.5). It is concluded that the combined effect of occupational solvent exposure and alcohol intake is probably an important cause of organic brain damage.

Relationships between three indicators of lead exposure in workers: blood lead, delta-aminolevulinic acid and free erythrocyte protoporphyrin.

Whole blood lead (Pb-B), urinary delta-aminolevulinic acid (ALA-U) and free erythrocyte protoporphyrin (FEP) were measured in three groups of workers (n = 196) with different degrees of exposure to lead, and one group of men with no previous exposure to the metal (n = 48). Inter-group comparison showed a correlation of r = 0.73 between Pb-B and log of ALA-U, and r = 0.91 between Pb-B and log of FEP. ALA-U and FEP values rose sharply after Pb-B values reached 450-500 micrograms/l.