Use of rodent carcinogenicity test results for determining potential cancer risk to humans.

Infante, Peter F.

doi:10.1289/ehp.93101s5143

“…However, behavior of a given chemical in specific individuals with unique biochemistry is difficult to predict from assay panel results. Animal testing is widely used but can over- or underestimate risk to humans because of species differences 8. Due to these difficulties, ~30% of new drug candidates fail due to toxicity issues that are not discovered until clinical testing.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Electrochemiluminescent Metabolic Toxicity Screening Arrays Using a Multiple Compound Set

Pan¹,

Zhao²,

Schenkman³

et al. 2011

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Arrays for screening metabolite-generated toxicity utilizing spots containing DNA, enzyme and electroluminescent (ECL) polymer ([Ru(bpy) 2 PVP 10 ] 2+ ) were extended to include a fully representative set of metabolic enzymes from human and rat liver microsomes, human and rat liver cytosol, and mouse liver S9 fractions. Array use involves two steps: (1) enzyme activation of the test chemical, and metabolite reaction with DNA, then (2) capture of ECL resulting from DNA damage using a CCD camera. Plots of ECL increase vs. enzyme reaction time monitor relative rates of DNA damage, and were converted into turnover rates for enzymic production of DNAreactive metabolites. ECL turnover rates were defined by R, the initial slope of ECL increase versus enzyme reaction time normalized for amounts of enzyme and test chemical. R-values were used to establish correlations for 11 toxic compounds with the standard toxicity metrics rodent liver TD 50 and LD 50 , Ames tests, and Comet assays for in vitro DNA damage. Results support the value of the ECL genotoxicity arrays together with toxicity bioassays for early screening of new chemicals and drug candidates.

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Occupational Chemical Carcinogenesis

Huff,

Melnick

2024

Patty's Toxicology

0

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Workers are exposed to carcinogens and carcinogenic exposure circumstances, as well as to many other agents considered probably, possibly, or reasonably anticipated to be human carcinogens. Covered herein are occupational carcinogens: chemicals, uncharacterized exposure circumstances, and occupations/workplaces known or suspected to cause cancer in workers, and agents causing cancers in animal bioassays, which are proven predictive for human cancers. Importantly, individuals differ in susceptibility for developing cancer due to exposure to a carcinogenic substance; factors influencing cancer outcomes include exposure circumstances, genetic differences, lifestyle, health condition, age, and gender. Identification of agents as carcinogens is based on information from epidemiological studies, long‐term animal studies, in vitro and in vivo evaluations, and assessments of mechanistic data and structure‐activity relationships. Various agencies, such as IARC, NTP, U.S. EPA, CalEPA, and others have developed classification schemes that categorize potential carcinogenicity of environmental and industrial agents in humans based on strength‐of‐evidence from human studies, animal studies, and mechanistic information. Categorizations formulated by authoritative bodies serve as the initial basis for standard's settings and regulatory actions. Several health and safety laws have been promulgated to protect workers from harmful effects of hazardous agents in the workplace. Risk characterization provides an integrative summary of available and relevant information on hazard identification, exposure assessment, and dose‐response relationships that have been used to estimate potential human cancer risks under various exposure circumstances. This information serves as the basis for risk management decisions on the extent to which workers' exposures to hazardous agents should be controlled. Likewise reducing or eliminating exposures to known and suspected carcinogens will reduce or prevent the incidences of occupational cancers. The World Health Organization reports occupational carcinogens are responsible for ∼152,000 cancer deaths per year and cancer prevention is essential because ∼40% of all cancer deaths can be prevented.

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Occupational Chemical Carcinogenesis

Huff¹,

Melnick²

2012

Patty's Toxicology

2

0

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Workers are exposed to carcinogens and carcinogenic exposure circumstances, as well as to many other agents considered probably, possibly, or reasonably anticipated to be human carcinogens. Covered herein are occupational carcinogens: chemicals, uncharacterized exposure circumstances, and occupations/workplaces known or suspected to cause cancer in workers, and agents causing cancers in animal bioassays, which are proven predictive for human cancers. Importantly, individuals differ in susceptibility for developing cancer due to exposure to a carcinogenic substance; factors influencing cancer outcomes include exposure circumstances, genetic differences, lifestyle, health condition, age, and gender. Identification of agents as carcinogens is based on information from epidemiological studies, long‐term animal studies, in vitro and in vivo evaluations, and assessments of mechanistic data and structure‐activity relationships. Various agencies, such as IARC, NTP, U.S. EPA, CalEPA, and others have developed classification schemes that categorize potential carcinogenicity of environmental and industrial agents in humans based on strength‐of‐evidence from human studies, animal studies, and mechanistic information. Categorizations formulated by authoritative bodies serve as the initial basis for standard's settings and regulatory actions. Several health and safety laws have been promulgated to protect workers from harmful effects of hazardous agents in the workplace. Risk characterization provides an integrative summary of available and relevant information on hazard identification, exposure assessment, and dose‐response relationships that have been used to estimate potential human cancer risks under various exposure circumstances. This information serves as the basis for risk management decisions on the extent to which workers' exposures to hazardous agents should be controlled. Likewise reducing or eliminating exposures to known and suspected carcinogens will reduce or prevent the incidences of occupational cancers. The World Health Organization reports occupational carcinogens are responsible for ∼152,000 cancer deaths per year and cancer prevention is essential because ∼40% of all cancer deaths can be prevented.

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Use of rodent carcinogenicity test results for determining potential cancer risk to humans.

Cited by 8 publications

References 26 publications

Evaluation of Electrochemiluminescent Metabolic Toxicity Screening Arrays Using a Multiple Compound Set

Evaluation of Electrochemiluminescent Metabolic Toxicity Screening Arrays Using a Multiple Compound Set

Occupational Chemical Carcinogenesis

Occupational Chemical Carcinogenesis

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