Comparison of Cancer Risks Projected from Animal Bioassays to Epidemiologic Studies of Acrylonitrile-Exposed Workers

Reconciling animal and human data in a cancer risk assessment of acrylonitrile

“…Even the results of the DuPont study with its older cohort and the 3-study summary (10) were not inconsistent with the animal-based risk estimate derived from the inhalation bioassay. In contrast, Collins & Strother (10) concluded that their summary of the NCI, Dutch, and DuPont studies was inconsistent with their animal-based risk estimate, and, earlier, Ward & Starr (9) concluded that a subset of the NCI study (28) was inconsistent with their animal-based risk estimate. Three factors contributed to the higher risks predicted by Collins & Strother (10) and Ward & Starr (9).…”

“…In 1993, Ward & Starr (9) concluded that the occupational epidemiologic studies had sufficient statistical power to detect the CNS cancer risk predicted from bioassays in which acrylonitrile was administered orally, and their analysis was updated in 1999 by Collins & Strother (10), who concluded likewise that the most recent epidemiologic studies were not consistent with the risk from acrylonitrile exposure predicted from animal data. Against this background, the American Conference of Government Industrial Hygienists (ACGIH) recently changed their classification of acrylonitrile from an A2 suspected human carcinogen to an A3 confirmed animal carcinogen with unknown relevance to humans (11) Because the route of exposure may be a key determinant of potency and because workers appear to be predominantly exposed by inhalation (1), this paper, in contrast to the analysis of Ward & Starr (9) or Collins & Strother (10), compares predictions from the inhalation bioassay in rats with CNS cancers observed in the 3 recent, large epidemiologic studies that included quantitative exposure levels for acrylonitrile-exposed workers.…”

“…For this purpose, we estimated the CNS cancer potency of acrylonitrile in rats on the basis of an inhalation bioassay (Quast J, Schuetz D, Balmer M, Gushow T, Park C, McKenna M. A two-year toxicity and oncogenicity study with acrylonitrile following inhalation exposure in rats. Prepared by the Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical, Midland, Michigan, United States, for the Chemical Manufacturing Association in 1980, unpublished observations) and, unlike Ward & Starr (9) or Collins & Strother (10), applied the potency to the actual observed follow-up time in the epidemiologic studies. By calculating the number of deaths predicted for the actual follow-up time of the workers and comparing them with the observed number of deaths and their confidence intervals, we explored the role of dose and follow-up time in explaining the apparently contradictory results for CNS cancer and exposure to acrylonitrile.…”

Cancer dose–response assessment for acrylonitrile based upon rodent brain tumor incidence: Use of epidemiologic, mechanistic, and pharmacokinetic support for nonlinearity

“…On the other hand, cancer bioassays in rats and mice consistently identify AN as a multi-site carcinogen following oral and inhalation exposures to high concentrations (>20 ppm in air; >30 ppm in water) Johannsen and Levinskas, 2002a,b;Maltoni et al, 1977Maltoni et al, , 1988Quast et al, 1980a,b). Several studies have been conducted in an attempt to evaluate this apparent discrepancy in a quantitative manner (Collins and Strother, 1999;Schulz et al, 2001;Ward and Starr, 1993). In comparing the results from eleven epidemiologic studies of AN-exposed workers to predicted brain tumor response from a rodent drinking water bioassay data, Ward and Starr (1993) concluded that, subject to certain caveats, the upper bound estimate of the inhalation cancer potency for AN is too high to be consistent with the human experience.…”

Mortality among chemical plant workers exposed to acrylonitrile and other substances

“…Environmental Protection Agency, 1990; Agency for Toxic Substances and Disease Registry, 1990b;Doll, 1991;Ward and Starr, 1993;Rothman, 1994;Blair and Kazerouni, 1997]. Also, four new or updated epidemiology studies [Benn and Osborne, 1998;Blair et al, 1998;Swaen et al, 1998;Wood et al, 1998] and a comprehensive meta-analysis [Collins and Acquavella, 1998] were presented at an August 1997 AN conference in Oxford, England [Doll, 1998].…”