Based on previous work, this paper aims to show how approximate methods of estimating exposure ca... more Based on previous work, this paper aims to show how approximate methods of estimating exposure can lead to a preliminary ranked list of chemicals for regulation of carcinogens. This list is likely to be more reliable, than those so far generated. The paper argues four main points. Firstly that an indication of the route by which the total production of
Pharmacokinetic analyses have recently been incorporated in risk assessments, with resultant risk... more Pharmacokinetic analyses have recently been incorporated in risk assessments, with resultant risks sometimes lower and associated “allowable” exposures much higher than would have been otherwise calculated. Preliminary investigations of the predictions of such models as they have been used for regulatory purposes are presented here. Precision is studied by treating parameters as random variables and performing Monte Carlo simulations and determining the range of estimates once parameter uncertainties are considered. Physiologically based pharmacokinetic models cannot be validated at low doses because low dose data in humans and test species are generally not available. Accuracy is discussed in terms of the assumptions and biases pertaining to low dose and interspecies extrapolation.
This study deals with the imprecision associated with estimating the risk of health effects due t... more This study deals with the imprecision associated with estimating the risk of health effects due to environmental causes. The major thrust revolves around the notion that the calculation of statistical risk, itself a probability, contains significant imprecision because of the cascade of error through the computations on which the risk, or probability of contracting a disease, is based. The cascade
... 0 U UJ LU UO (N ' r^ ^ fS -^ s^ UI UI u^ r^ (N "-i ^s UI U ^ UJ U) u-rs| fi r-,1 Ie... more ... 0 U UJ LU UO (N ' r^ ^ fS -^ s^ UI UI u^ r^ (N "-i ^s UI U ^ UJ U) u-rs| fi r-,1 Ie SUU uo 2 u gsggSS ^gl-gj^cli uuucccd cd eo HC 5 u ... 19: Risk quanti-tation and regulatory policy (edited by Hoel DG, Merrill RA and Perera FP), Cold Spring Harbor Laboratory, Cold Spring Harbor, pp ...
Urethane (ethyl carbamate) is a contaminant of alcoholic beverages and other fermentation product... more Urethane (ethyl carbamate) is a contaminant of alcoholic beverages and other fermentation products. It is genotoxic, causing mutations and chromosome damage in vivo, and acts as an initiator in initiation-promotion bioassays. However, mutations are not consistently observed in vitro, probably because the standard activation system is inappropriate. Nearly two hundred positive urethane carcinogenicity bioassays were identified in the literature, in which tumors were observed at multiple sites in many species. The 25 studies using oral dosing (in drinking water or feed, or by gavage) were examined, and 40 data sets suitable for potency estimation were identified. Only the studies by Schmahl et al. in rats and mice involved more than one concurrent dose level in addition to controls. Dose levels, study durations and dosing periods among the selected studies varied widely. A saturable detoxification pathway is the primary route of urethane metabolism, while carcinogenesis apparently results from a separate minor pathway. A pharmacokinetic model was constructed based on reported kinetics of urethane metabolism in rats and mice. In estimating the carcinogenic potency of urethane at low doses, a pharmacokinetic correction based on this model was applied. In addition, to account for variable dosing, study duration and reporting, time-dependent models were used. The mouse lung was the site most sensitive to urethane carcinogenesis. A number of relatively consistent human cancer potency values were estimated, in the range 0.1 − 3.0 (mg/kg-day)−1. Upper bounds and measures of central tendency of the distribution of potencies were calculated and compared to the estimate based on the single most sensitive study. These procedures suggest an overall potency estimate of 1 (mg/kg-day)−1 for urethane, and that an intake of 0.7 μg urethane per day by an adult is associated with a cancer risk of 1 in 105.
Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these ch... more Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design. Objectives: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches. Methods: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development. Results and Discussion: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed. https://doi.org/10.1289/EHP8525
Based on previous work, this paper aims to show how approximate methods of estimating exposure ca... more Based on previous work, this paper aims to show how approximate methods of estimating exposure can lead to a preliminary ranked list of chemicals for regulation of carcinogens. This list is likely to be more reliable, than those so far generated. The paper argues four main points. Firstly that an indication of the route by which the total production of
Pharmacokinetic analyses have recently been incorporated in risk assessments, with resultant risk... more Pharmacokinetic analyses have recently been incorporated in risk assessments, with resultant risks sometimes lower and associated “allowable” exposures much higher than would have been otherwise calculated. Preliminary investigations of the predictions of such models as they have been used for regulatory purposes are presented here. Precision is studied by treating parameters as random variables and performing Monte Carlo simulations and determining the range of estimates once parameter uncertainties are considered. Physiologically based pharmacokinetic models cannot be validated at low doses because low dose data in humans and test species are generally not available. Accuracy is discussed in terms of the assumptions and biases pertaining to low dose and interspecies extrapolation.
This study deals with the imprecision associated with estimating the risk of health effects due t... more This study deals with the imprecision associated with estimating the risk of health effects due to environmental causes. The major thrust revolves around the notion that the calculation of statistical risk, itself a probability, contains significant imprecision because of the cascade of error through the computations on which the risk, or probability of contracting a disease, is based. The cascade
... 0 U UJ LU UO (N ' r^ ^ fS -^ s^ UI UI u^ r^ (N "-i ^s UI U ^ UJ U) u-rs| fi r-,1 Ie... more ... 0 U UJ LU UO (N ' r^ ^ fS -^ s^ UI UI u^ r^ (N "-i ^s UI U ^ UJ U) u-rs| fi r-,1 Ie SUU uo 2 u gsggSS ^gl-gj^cli uuucccd cd eo HC 5 u ... 19: Risk quanti-tation and regulatory policy (edited by Hoel DG, Merrill RA and Perera FP), Cold Spring Harbor Laboratory, Cold Spring Harbor, pp ...
Urethane (ethyl carbamate) is a contaminant of alcoholic beverages and other fermentation product... more Urethane (ethyl carbamate) is a contaminant of alcoholic beverages and other fermentation products. It is genotoxic, causing mutations and chromosome damage in vivo, and acts as an initiator in initiation-promotion bioassays. However, mutations are not consistently observed in vitro, probably because the standard activation system is inappropriate. Nearly two hundred positive urethane carcinogenicity bioassays were identified in the literature, in which tumors were observed at multiple sites in many species. The 25 studies using oral dosing (in drinking water or feed, or by gavage) were examined, and 40 data sets suitable for potency estimation were identified. Only the studies by Schmahl et al. in rats and mice involved more than one concurrent dose level in addition to controls. Dose levels, study durations and dosing periods among the selected studies varied widely. A saturable detoxification pathway is the primary route of urethane metabolism, while carcinogenesis apparently results from a separate minor pathway. A pharmacokinetic model was constructed based on reported kinetics of urethane metabolism in rats and mice. In estimating the carcinogenic potency of urethane at low doses, a pharmacokinetic correction based on this model was applied. In addition, to account for variable dosing, study duration and reporting, time-dependent models were used. The mouse lung was the site most sensitive to urethane carcinogenesis. A number of relatively consistent human cancer potency values were estimated, in the range 0.1 − 3.0 (mg/kg-day)−1. Upper bounds and measures of central tendency of the distribution of potencies were calculated and compared to the estimate based on the single most sensitive study. These procedures suggest an overall potency estimate of 1 (mg/kg-day)−1 for urethane, and that an intake of 0.7 μg urethane per day by an adult is associated with a cancer risk of 1 in 105.
Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these ch... more Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design. Objectives: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches. Methods: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development. Results and Discussion: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed. https://doi.org/10.1289/EHP8525
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