Quantifying uncertainty in a risk assessment using human data.

A call for risk assessment approaches that better characterize and quantify uncertainty has been made by the scientific and regulatory community. This paper responds to that call by demonstrating a distributional approach that draws upon human data to derive potency estimates and to identify and quantify important sources of uncertainty. The approach is rooted in the science of decision analysis and employs an influence diagram, a decision tree, probabilistic weights, and a distribution of point estimates of carcinogenic potency. Its results estimate the likelihood of different carcinogenic risks (potencies) for a chemical under a specific scenario. For this exercise, human data on formaldehyde were employed to demonstrate the approach. Sensitivity analyses were performed to determine the relative impact of specific levels and alternatives on the potency distribution. The resulting potency estimates are compared with the results of an exercise using animal data on formaldehyde. The paper demonstrates that distributional risk assessment is readily adapted to situations in which epidemiologic data serve as the basis for potency estimates. Strengths and weaknesses of the distributional approach are discussed. Areas for further application and research are recommended.

Quantitative risk assessment for a glass fiber insulation product.

California Proposition 65 (Prop65) provides a mechanism by which the manufacturer may perform a quantitative risk assessment to be used in determining the need for cancer warning labels. This paper presents a risk assessment under this regulation for professional and do-it-yourself insulation installers. It determines the level of insulation glass fiber exposure (specifically Owens Corning's R-25 PinkPlus with Miraflex) that, assuming a working lifetime exposure, poses no significant cancer risk under Prop65's regulations. "No significant risk" is defined under Prop65 as a lifetime risk of no more than one additional cancer case per 100,000 exposed persons, and nonsignificant exposure is defined as a working lifetime exposure associated with "no significant risk." This determination can be carried out despite the fact that the relevant underlying studies (i.e., chronic inhalation bioassays) of comparable glass wool fibers do not show tumorigenic activity. Nonsignificant exposures are estimated from (1) the most recent RCC chronic inhalation bioassay of nondurable fiberglass in rats; (2) intraperitoneal fiberglass injection studies in rats; (3) a distributional, decision analysis approach applied to four chronic inhalation rat bioassays of conventional fiberglass; (4) an extrapolation from the RCC chronic rat inhalation bioassay of durable refractory ceramic fibers; and (5) an extrapolation from the IOM chronic rat inhalation bioassay of durable E glass microfibers. When the EPA linear nonthreshold model is used, central estimates of nonsignificant exposure range from 0.36 fibers/cc (for the RCC chronic inhalation bioassay of fiberglass) through 21 fibers/cc (for the i.p. fiberglass injection studies). Lower 95% confidence bounds on these estimates vary from 0.17 fibers/cc through 13 fibers/cc. Estimates derived from the distributional approach or from applying the EPA linear nonthreshold model to chronic bioassays of durable fibers such as refractory ceramic fiber or E glass microfibers are intermediate to the other approaches. Estimates based on the Weibull 1.5-hit nonthreshold and 2-hit threshold models exceed by at least a factor of 10 the corresponding EPA linear nonthreshold estimates. The lowest nonsignificant exposures derived in this assessment are at least a factor of two higher than field exposures measured for professionals installing the R-25 fiberglass insulation product and are orders of magnitude higher than the estimated lifetime exposures for do-it-yourselfers.

Case-control study of cancer risk in tetraethyl lead manufacturing.

A case-control study was conducted to investigate the relative risk of cancer detection among Du Pont employees who worked in a tetraethyl lead (TEL) manufacturing area. The study's objective was to determine whether the employees' risk of developing or dying from cancer was associated with occupational exposure to TEL. All malignant neoplasms detected in the active and pensioned employee population during the period 1956-1987 were studied. TEL exposure was estimated by the following measures: ever employed in the TEL area, years of employment in TEL, TEL exposure rank, and the TEL cumulative exposure index. TEL manufacturing exposed employees to both organic and inorganic lead compounds. Because the underlying data did not permit the exposure assessment to distinguish between organic and inorganic lead, the TEL exposure measures reflect exposure to the TEL manufacturing process itself. The effects of latency, cigarette smoking habits, and exposures to other known or suspected carcinogens at the plant were also assessed. A strong association was observed between exposure to the TEL manufacturing process and rectal cancer (the odds ratio was 3.7 with 90% confidence limits of 1.3-10.2 for the analysis of ever/never exposed to TEL). An exposure-response relationship was noted with a fourfold elevation in the odds ratio at the high-very high cumulative exposure level. These patterns were even more pronounced after assuming a 10 year latency. Similar results were obtained for cancers of the sigmoid colon. These findings suggest that exposure to the TEL manufacturing process may have played a causal role in the colorectal cancer experience at the plant. This position is supported by the graded exposure-response relationships, the consistency of the results across exposure measures, the specificity of the health outcome (i.e., colorectal cancer), and the strength of the association. However, the evidence for causality is not compelling. This is the first report of an association between TEL manufacturing and colorectal cancer, and the evidence is compatible with a wide range of causal (i.e., indirect vs. direct acting; initiating vs. promoting) and noncausal (i.e., statistical and methodological bias; coincidence) interpretations.

Epidemiologic study of lung cancer mortality in workers exposed to titanium tetrachloride.

A study was done to examine whether workers exposed to titanium tetrachloride had significantly higher risks of lung cancer, chronic respiratory disease, pleural thickening/plaques, or pulmonary fibrosis than referent groups. A total of 2477 employees from two titanium dioxide plants were studied. Of that group, 969 employees exposed to titanium tetrachloride were observed from 1956 through 1985 for cancer and chronic respiratory disease incidence and from 1935 through 1983 for mortality. A cross-sectional sample of 398 employees was evaluated for chest roentgenogram abnormalities. Cohort analyses showed that the risk of developing lung cancer and other fatal respiratory diseases was not statistically significantly higher for the titanium tetrachloride-exposed workers than for the referent group. Nested case-control analyses found no statistically significant association between titanium tetrachloride exposure and risk of lung cancer, chronic respiratory disease, and chest roentgenogram abnormalities. No cases of pulmonary fibrosis were observed among titanium tetrachloride-exposed employees. Smoking was found to be a strong predictor of lung cancer mortality in the nonexposed employees with an increased risk of dying from lung cancer up to 7-fold higher in current smokers than in nonsmokers.

A survey of the prevalence of epididymitis in an industrial setting.

In response to concerns about the occurrence of epididymitis among employees at a Du Pont textile fibers plant, information was obtained from 1342 (94.8%) active male employees on history of epididymitis and/or orchitis (6.8%), prostatitis (11.5%), other genitourinary conditions, and vasectomy. Vasectomy was associated with an odds ratio of 3.26 (90% confidence interval (CI) = 1.96, 5.43) for subsequent development of epididymitis. History of prostatitis was also a risk factor for epididymitis (odds ratio = 5.02, 90% CI = 2.94, 8.58).

Issues in data sharing and access: an industry perspective.

Epidemiologic data sharing and access, and information sharing and access, are complex issues with no consensus within the industrial community. The purpose of this paper is to provide an introduction, as well as some personal perspectives, to the issues of data access and sharing. These perspectives include a discussion of types of data sharing, advantages and barriers to openness, and alternatives that lower the need for sharing of the raw data.

A case-control study of cancer among du pont employees with potential for exposure to dimethylformamide.

This case-control study was undertaken to determine whether the risk of developing cancers of the buccal cavity and pharynx (N = 39), liver (N = 6), prostate (N = 43), testis (N = 11), or malignant melanoma of the skin (N = 39) is related to exposure to dimethylformamide (DMF). Case and control subjects were obtained from four Du Pont plants. DMF is produced at one plant and used at the other three. Cancer cases identified from the company Cancer Registry comprise those reported among active male employees at the study plants during 1956 to 1985. For each case, two control subjects were selected, matched on sex, payroll class (wage or salary), birth year, and plant. To determine whether an employee could have been exposed to DMF during his career at the plant, all jobs with potential for exposure to DMF were identified. Each job was assigned an exposure ranking based on DMF industrial hygiene air monitoring, DMF metabolite (measured as N-methylformamide in urine) monitoring, and knowledge of the evolution of manufacturing processes and workplace exposure controls. Each employee's DMF exposure pattern was then characterized as (a) ever v never having been exposed to DMF and (b) highest DMF exposure experienced. Summary analyses for all plants combined showed no statistically significant association between ever having been exposed to DMF and subsequent development of cancers of the buccal cavity and pharynx, liver, malignant melanoma, prostate, and testis. Examined by plant site, prostate cancer at one plant was significantly elevated, based on three case subjects exposed out of four.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiologic study of workers exposed to titanium dioxide.

The objective of this study was to determine whether workers exposed to titanium dioxide (TiO2) had significantly higher risks of lung cancer, chronic respiratory disease, pleural thickening/plaques, or pulmonary fibrosis than referent groups. A total of 1,576 employees exposed to TiO2 were observed from 1956 through 1985 for cancer and chronic respiratory disease incidence, and from 1935 through 1983 for mortality. A cross-sectional sample of 398 employees was evaluated for chest roentgenogram abnormalities. Cohort analyses suggested that the risks of developing lung cancer and other fatal respiratory diseases were no higher for TiO2-exposed employees than for the referent groups. Nested case-control analyses found no statistically significant associations between TiO2 exposure and risk of lung cancer, chronic respiratory disease, and chest roentgenogram abnormalities. No cases of pulmonary fibrosis were observed among TiO2-exposed employees.

Cancer incidence of workers exposed to dimethylformamide and/or acrylonitrile.

This study was to determine whether exposure to dimethylformamide (DMF) and acrylonitrile (ACN) separately or in combination, was associated with increased cancer incidence. Workers exposed to DMF and/or ACN were observed from 1956 through 1984 for cancer incidence. The workers exposed to DMF but not ACN showed significant excesses in incidence for buccal cavity and pharynx cancer and malignant melanoma. A significant excess of prostate cancer incidence was observed among workers exposed to DMF and ACN. No dose-response relationships were observed between DMF or ACN exposure and cancer incidence. The significant excesses in cancer incidence among employees exposed to DMF and/or ACN could be due to statistical chance or other factors, such as tobacco and alcohol consumption. Further studies are warranted.

Mortality study of workers exposed to dimethylformamide and/or acrylonitrile.

Workers exposed to dimethylformamide (DMF) and/or acrylonitrile (ACN) were observed from 1950 through 1982 for mortality. The wage-roll workers exposed to DMF showed significant excess in total deaths attributable mainly to ischemic heart disease and external causes when compared with rates from E. I. Du Pont de Nemours & Co. However, there were no significant excesses in mortality when expected numbers were based on US or local statistics. No dose-response relationships were observed between DMF or ACN exposure and mortality. The significant excesses in mortality among employees exposed to DMF and/or ACN could be due to statistical chance or life-style factors

Trends in the incidence of myocardial infarction and in associated mortality and morbidity in a large employed population, 1957-1983.

We analyzed long-term trends in the incidence of a first acute myocardial infarction and in case-fatality rates among employees of the Du Pont Company from 1957 through 1983. A steady decline in incidence was observed among male employees. The annual age-adjusted rate in the 1957-1959 period was 3.19 per 1000, as compared with 2.29 per 1000 in the 1981-1983 period--a decline of 28.2 per cent. The rate of decline was higher among salaried (white-collar) employees than among production workers receiving hourly wages. No trend was seen among female employees, but the number of cases may have been to small to detect a decline. Beginning in 1969, the 24-hour case-fatality rate showed a moderate decline, but after 1975, there was a sharp drop in the 30-day case-fatality rate among persons who survived 24 hours after the attack. These declines did not begin until several years after the decline in incidence had begun. This study and others suggest that improved medical care probably made some contribution to the decline in mortality associated with coronary heart disease, but the major source of the decline has been a reduction in the incidence of the disease.