Cancer risk assessment human relevancy

Monte Carlo simulation, an iterative technique which derives a range of risk estimates, was incorporated into a trichloroethylene risk assessment using the PBPK model developed by Fisher and Allen (1993). The results of this study (Cronin et al. 1995), which used the kinetics of TCA production and trichloroethylene elimination as the dose metrics relevant to carcinogenic risk, indicated that concentrations of 0.09-1.0 pg/L (men) and 0.29-5.3 pg/L (women) in drinking water correspond to a cancer risk in humans of 1 in 1 million. For inhalation exposure, a similar risk was obtained from intermittent exposure to 0.07-13.3 ppb (men) and 0.16-6.3 ppb (women), or continuous exposure to 0.01-2.6 ppb (men) and 0.03-6.3 ppb (women) (Cronin et al. 1995). 

Two examples of alternative approaches to cancer risk assessment would be estimations based on threshold-response (EPA, 2005a) and benchmark dose modeling (EPA, 1995, 2000). As a practical matter, if the proposed basis of safety relies on a threshold or mode-of-action characterization to dismiss or mitigate animal tumor data, PDA would reconunend that the safety narrative clearly discuss the scientific rationale and present all relevant data for consideration. In the absence of adequate evidence to the contrary, PDA presumes that certain assumptions are appropriately protective of safety, namely that (i) the induction of tumors in animals is relevant to human... 

Although the term mode of action appears sometimes in the context of noncancer effects, it finds particular use in the context of cancer risk assessment, where mode of action forms the basis for (1) determining whether tumors observed in animals are relevant to humans, and (2) determining the approach for quantitative cancer risk assessment. IPCS has developed a conceptual framework for evaluation mode of action for chemical carcinogenesis, based partly on a modification of the Bradford-Hill criteria for causality. A similar approach is used by the US EPA. Under this framework, each mode of action is analyzed separately, noting that multiple modes of action may contribute to the development of a given tumor type, and that a single chemical may cause tumors in different tissues by different modes of action. This framework includes ... 

The majority of the tumor data available for conducting cancer risk assessments for exposure to enviromnental chemicals come from 2-year cancer bioassays using rats and mice. Thus, a MOA based on key events is inevitably developed for laboratory animals and not humans. There are, of course, a few exceptions for which human tumor data are available (NTP 2005). These human data are generally used together with rodent tumor data as part of dose-response characterization. Thus, the need in all cases is to demonstrate that the animal MOA is plausible in humans. This can be accomplished by use of a human relevance framework (described below in this section and in Table 13.1 and in Eigure 13.1). 

Dietrich, D. R. (1995). Alpha 2u-globuhn Species- and sex-specific protein synthesis and excretion, association with chemically induced renal toxicity and neoplasia in the male rat and relevance in human cancer risk assessment. Rev Biochem Toxicol 11, 115-180. 

Thus, in assessing potential bladder cancer risk for humans based on studies in rodents, consideration of a threshold dose response is the foremost consideration. The differences in composition of the urine, anatomic differences, and especially exposure differences between rodents and humans must be taken into account. Furthermore, the evidence for a relationship for urinary tract calculi to an increased risk of bladder cancer is relatively weak and is complicated by the usual association of bacterial cystitis with the presence of long-standing calculi. Urinary precipitate and crystals are not relevant to human carcinogenesis, in contrast to rodents. 

BorghoffSJ. 1993. 2u-Globulin-mediated male rat nephropathy and kidney cancer relevance to human risk assessment. Chemical Industry Institute of Technology (CUT) Activities 1-8. 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

The Monographs represent the first step in carcinogenic risk assessment, which involves examination of all relevant information in order to assess the strength of the available evidence that certain exposures could alter the incidence of cancer in humans. The second step is quantitative risk estimation. Detailed, quantitative evaluations of epidemiological data may be made in the Monographs, but without extrapolation beyond the range of the data available. Quantitative extrapolation from experimental data to the human situation is not undertaken. 

Henderson RF, Sabourin PJ, Medinsky MA, et al. 1992. Benzene dosimetry in experimental animals Relevance for risk assessment. In D Amato R, Slaga TJ, FarlandWH, et al. Relevance of animal studies to the evaluation of human cancer risk. New York, NY Wiley-Liss Inc. 93-105. 

Studies of occupational exposures to sulfur mustard indicate an elevated risk of respiratory tract and skin tumors following long-term exposure to acutely toxic concentrations. Overall, several factors are important regarding the assessment of the carcinogenicity of sulfur mustard. Increased cancer incidence in humans appears to be associated only with exposures that caused severe acute effects, and occupational exposures tended to involve repeated exposures and repeated injury of the same tissues. Because the therapeutic use of the sulfur mustard analog nitrogen mustard is associated with an increased incidence of CML, the reports of CML in HD-exposed individuals appear to be relevant to the eareinogenicity of sulfur mustard. 

A 2 year cancer bioassay in mice that employed a single dose of 500 ppm for 5 min day 5 days week for the duration of the study reported seeing an increase in lung tumors. This study is not considered adequate to conduct a meaningful assessment of cancer risk from SO2 in human populations, and its relevance to human risk is not known. 

TERA scientists analyze available human and animal toxicity data to determine the potential for human health effects from exposure to chemicals. These assessments can include hazard assessments and deter-mination/evaluations of mode of action and weight of evidence determinations for relevance of particular endpoints/effects to humans from environmental or occupational exposures. When adequate data are available, TERA derives noncancer and cancer risk estimates for various routes of exposure. TERA frequently publishes the results of the finalized assessment in peer reviewed journals and posts the assessments on its website. 

In the absence of human data (the most preferred data for risk assessment), the dose-response assessment for either cancer or noncancer toxicity is determined from animal toxicity studies using an animal model that is relevant to humans or using a critical study and species that show an adverse effect at the lowest administered dose. The default assumption is that humans may be as sensitive as the most sensitive experimental species. 

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