Cancer risk assessment for 1,3-butadiene: Dose–response modeling from an epidemiological perspective

2007 ◽  
Vol 166 (1-3) ◽  
pp. 140-149 ◽  
Author(s):  
Robert L. Sielken ◽  
Ciriaco Valdez-Flores ◽  
Michael L. Gargas ◽  
Christopher R. Kirman ◽  
M. Jane Teta ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Cancer Risk ◽  
Dose Response ◽  
Cancer Risk Assessment ◽  
Response Modeling

Sources of Uncertainty in Dose-Response Modeling of Epidemiological Data for Cancer Risk Assessment

1999 ◽  
Vol 895 (1 UNCERTAINTY I) ◽  
pp. 212-222 ◽  
Author(s):  
LESLIE STAYNER ◽  
A. JOHN BAILER ◽  
RANDALL SMITH ◽  
STEPHEN GILBERT ◽  
FAYE RICE ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Cancer Risk ◽  
Dose Response ◽  
Epidemiological Data ◽  
Cancer Risk Assessment ◽  
Sources Of Uncertainty ◽  
Response Modeling

scholarly journals Cancer risk assessment: Optimizing human health through linear dose–response models

2015 ◽  
Vol 81 ◽  
pp. 137-140 ◽  
Author(s):  
Edward J. Calabrese ◽  
Dima Yazji Shamoun ◽  
Jaap C. Hanekamp
Keyword(s):  
Risk Assessment ◽  
Cancer Risk ◽  
Human Health ◽  
Dose Response ◽  
Cancer Risk Assessment ◽  
Response Models ◽  
Linear Dose

scholarly journals Hormesis: Implications for Cancer Risk Assessment

Dose-Response ◽  
2005 ◽  
Vol 3 (3) ◽  
pp. dose-response.0 ◽  
Author(s):  
Jonathan Borak ◽  
Greg Sirianni
Keyword(s):  
Risk Assessment ◽  
Cancer Risk ◽  
Dose Response ◽  
Low Dose ◽  
Cancer Risk Assessment ◽  
Response Curves ◽  
Response Characteristics ◽  
Non Linear ◽  
Dose Responses ◽  
Current Guidelines

Current guidelines for cancer risk assessment emphasize a toxicant's “mode of action”, rather than its empirically derived dose-response relationship, for determining whether linear low-dose extrapolation is appropriate. Thus, for reasons of policy, demonstration of hormesis is generally insufficient to justify a non-linear approach, although it may provide important insights into the actions of toxicants. We evaluated dose-response characteristics of four carcinogens reported to have hormetic dose-response curves: cadmium chloride; ionizing radiation; PAHs; and, 2,3,7,8-TCDD. For each, the study that documented hormesis in one organ also provided evidence of non-hormetic dose-responses in other organs or non-hormetic responses for seemingly similar carcinogens in the same species and organs. Such inconsistency suggests toxicologic reasons that the finding of hormesis alone is not sufficient to justify use of non-linear low-dose extrapolations. Moreover, available data in those examples are not sufficient to know whether hormesis is a property of the toxicants, the target organ, or the exposed species. From the perspectives of cancer risk assessment, the greatest informational value of hormesis may be that it provokes mechanistic studies intended to explain why hormesis occurs.

scholarly journals Requirements for a Biologically Realistic Cancer Risk Assessment for Inorganic Arsenic

1999 ◽  
Vol 18 (2) ◽  
pp. 131-147 ◽  
Author(s):  
Harvey J. Clewell ◽  
P. Robinan Gentry ◽  
Hugh A. Barton ◽  
Annette M. Shipp ◽  
Janice W. Yager ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Risk Assessment ◽  
Cancer Risk ◽  
Dose Response ◽  
Cell Cycle Control ◽  
Inorganic Arsenic ◽  
Cancer Risk Assessment ◽  
Strong Nonlinearity ◽  
Experimental Animals ◽  
Highly Nonlinear

A remarkable feature of the carcinogenicity of inorganic arsenic (As,) is the observation that human exposures to Asi have been strongly associated with increases in skin, lung, and internal cancers, but As, does not typically cause tumors in standard laboratory animal test protocols. Considerable controversy has centered on whether there is epidemiological evidence of a “threshold” for the carcinogenic effects of Asi, or at least of a highly nonlinear dose–response. Saturation of metabolism in the dose-range associated with tumors does not appear to be adequate to produce a major impact on the dose-response for carcinogenicity. If there is a strong nonlinearity, it results from the nature of the carcinogenic mechanism(s) of Asi. However, no single hypothesis for the mechanism of Asi carcinogenicity has widespread support. A biologically realistic cancer risk assessment for Asi would requirea quantitative description of the dose of active arsenic species in target tissues, the interactions between active arsenic and tissue constituents, and the manner in which these interactions result in tumor formation in multiple organs in humans, but not in experimental animals. Although Asi has only infrequently been associated with tumors in animal studies, it has repeatedly been shown to act as a comutagen in vitro and as a cocarcinogen in vivo. Asi is clastogenic, producing chromatid aberrations, but does not produce point mutations at single gene loci. Of particular interest, Asi has been shown to inhibit repair of DNA single-strand breaks, a possible mechanism for its observed comutagenicity and cocarcinogenicity. We propose a cocarcinogenic mode of action in which Asi acts primarily on intermediate cells deficient in cell cycle control at a late stage in a preexisting carcinogenic process. This interaction enhances ge-nomic fragility and accelerates conversion of premalignant lesions to more aggressive, clinically observable tumors. An indirect effect of As, on DNA repair is consistent with the expectation of a nonlinear dose-response rather than the linear dose-response traditionally assumed for mutagenic carcinogens. However, defining the exact nature of this tumor dose-response will require further experimental data on the dose-response for the cellular effects of Asi. Because Asi carcinogenicity is unlikely to be observed in normal experimental animals not exposed to other carcinogens, studies in animals and cell lines deficient in cell cycle control should also be considered. Experimental studies specifically designed to address the key mechanistic and dose-response issues for Asi carcinogenicity are critically needed to support public health policy decisions regarding current environmental exposures to Asi.

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