Virtually Safe Dose Research Articles

A Nationwide Survey and Risk Assessment of Ethyl Carbamate Exposure Due to Daily Intake of Alcoholic Beverages in the Chinese General Population.

Ethyl carbamate (EC) is carcinogenic, and, in China, oral intake of EC mainly occurs as a result of the consumption of alcoholic beverages. To obtain the latest EC intake and risk analysis results for the general population in China, the China National Center for Food Safety Risk Assessment (CFSA) conducted the sixth total diet study (TDS) as a platform to analyze EC contents and exposure due to the intake of alcoholic beverages. A total of 100 sites in 24 provinces were involved in the collection and preparation of alcohol mixture samples for the sixth TDS. There were 261 different types of alcohol collected across the country, based on local dietary menus and consumption survey results. Ultimately, each province prepared a mixed sample by mixing their respective samples according to the percentage of local consumption. The EC levels of these twenty-four mixed samples were determined using our well-validated gas chromatography-mass spectrometry (GC-MS) method. The values ranged from 1.0 μg/kg to 33.8 μg/kg, with 10.1 μg/kg being the mean. China's EC daily intake ranged from 0.001 ng/kg bw/d to 24.56 ng/kg bw/d, with a mean of 3.23 ng/kg bw/d. According to the margin of exposure (MOE), virtually safe dose (VSD), and T25 risk assessments of the carcinogenicity of EC, the mean lifetime cancer risk for the Chinese population was 9.8 × 104, 1.5 × 10-7, and 8.6 × 10-8, respectively. These data show that the carcinogenicity of EC in the general Chinese population due to alcoholic intake is essentially minimal.

Probabilistic methods for non-cancer health effects

Noncancer risk assessment methods and harmonization with cancer assessment methods have advanced from the simple divide a No Observed Adverse Effect Level (NOAEL) by a default safety factor or a linear extrapolation to background of the early 1980's. This advance is due in part due to groups such as the American Industrial Health Council, the National Institute of Environmental Health Sciences, the Society for Risk Analysis, the Society of Toxicology, and the U.S. Environmental Protection Agency, the National Academy of Sciences (NAS), the International Programme on Chemical Safety, and to many independent researchers outside of and within a workshop series sponsored by the Alliance for Risk Assessment prompted by the NAS \\. Several of the case studies from this workshop series, and earlier work such as Bogdanffy et al., demonstrate that the dose response assessment of non-cancer toxicity and the harmonization of cancer and non-cancer methods are more than just a simple reflection of treating all non-cancer toxicity as if it has a threshold, or all cancer toxicity as if it did not. Moreover, one recommendation of NAS \\ was to develop a problem formulation with risk managers prior to conducting any risk assessment. If the development of this problem formulation only necessitates the determination of a safe, or virtually safe dose, then the estimation of a Reference Dose (RfD) or virtually safe dose (VSD) or similar constructs should be encouraged. Not all of our environmental problems need a precise quantitative solution.

Tolerability of risk: A commentary on the nitrosamine contamination issue.

For decades, regulators have grappled with different approaches to address the issue of control of impurities. Safety-based limits, such as permissible daily exposure (PDE), acceptable intake (AI), threshold of toxicological concern (TTC) and less than lifetime limits (LTL) have all been used. For many years these safety-based limits have been recognized as virtually safe doses (VSDs). Recently, however, many regulatory agencies are seeking to impose limits for N-nitrosamine impurities, which are significantly below the VSD. This commentary will discuss the evolution of safety-based limits for impurities, provide an overview of the valsartan N-nitrosamine contamination issue and review the toxicology of N-nitrosamines. The outcome of a lessons-learned exercise on sartan medications undertaken by the European Medicines Agency (EMA) will also be discussed. The review will also highlight the many analytical challenges inherent with controlling impurities to ppb-based limits. The use of highly sensitive, low ppb limits, methods may lead to future issues of batch rejection, based on false positives. Regulators initially viewed the N-nitrosamine risk as being insufficient to prompt immediate product discontinuation and patients were specifically advised to continue using their affected medication. Patients were also informed that exposure to N-nitrosamines is extremely common via food and drinking water.

A new approach for risk assessment of aggregate dermal exposure to banned azo dyes in textiles

A semi-quantitative risk assessment of banned azo dyes in textiles was performed to assess the health risk when consumers have direct dermal contact with these products. A novel model, which includes three exposure scenarios, was proposed to estimate the absorption of leachable azo dyes from twenty textiles samples. The effective daily uptakes of benzidine from sample 1 and sample 19 in chronic exposure model were 0.318 ng/kg-day and 0.011 ng/kg-day, respectively. Compared to virtually safe dose (VSD), the corresponding cancer risks were 7.42 × 10−5 (Sample 1) and 2.56 × 10−6 (Sample 19). As noted by nomograph assessment, the health risk induced by long-term exposure of banned azo dyes from textiles was at the range of "very low" to "low". In short-term exposure cases, the risks were acceptable though the amount of detected aromatic amines was relatively high in particular samples. The amount of exposure and the risk level might be overestimated as a series of assumptions were made under extreme conditions.

Development and validation of an improved method for the determination of chloropropanols in paperboard food packaging by GC-MS

The objective of this study was to develop an improved analytical method for the determination of 3-chloro-1,2-propanediol (3-MCPD) and 1,3-dichloropropanol (1,3-DCP) in paper-type food packaging. The established method includes aqueous extraction, matrix spiking of a deuterated surrogate internal standard (3-MCPD-d5), clean-up using ExtrelutTM solid-phase extraction, derivatisation using a silylation reagent, and GC-MS analysis of the chloropropanols as their corresponding trimethyl silyl ethers. The new method is applicable to food-grade packaging samples using European Commission standard aqueous extraction and aqueous food stimulant migration tests. In this improved method, the derivatisation procedure was optimised; the cost and time of the analysis were reduced by using 10 times less sample, solvents and reagents than in previously described methods. Overall the validation data demonstrate that the method is precise and reliable. The limit of detection (LOD) of the aqueous extract was 0.010 mg kg−1 (w/w) for both 3-MCPD and 1,3-DCP. Analytical precision had a relative standard deviation (RSD) of 3.36% for 3-MCPD and an RSD of 7.65% for 1,3-DCP. The new method was satisfactorily applied to the analysis of over 100 commercial paperboard packaging samples. The data are being used to guide the product development of a next generation of wet-strength resins with reduced chloropropanol content, and also for risk assessments to calculate the virtual safe dose (VSD).

Occupational risk assessment: Threshold and non-threshold models for the mutagenic effect of epoxides and consequences for the determination of a virtual safe dose

Occupational risk assessment: Threshold and non-threshold models for the mutagenic effect of epoxides and consequences for the determination of a virtual safe dose

Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat

This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were compared with those of a previously developed PBK model for methyleugenol (ME) in male rat. The results obtained reveal that formation of 1′-hydroxymethyleugenol glucuronide (1′HMEG), a major metabolic pathway in male rat liver, appears to represent a minor metabolic pathway in human liver whereas in human liver a significantly higher formation of 1′-oxomethyleugenol (1′OME) compared with male rat liver is observed. Furthermore, formation of 1′-sulfooxymethyleugenol (1′HMES), which readily undergoes desulfonation to a reactive carbonium ion (CA) that can form DNA or protein adducts (DA), is predicted to be the same in the liver of both human and male rat at oral doses of 0.0034 and 300mg/kg bw. Altogether despite a significant difference in especially the metabolic pathways of the proximate carcinogenic metabolite 1′-hydroxymethyleugenol (1′HME) between human and male rat, the influence of species differences on the ultimate overall bioactivation of methyleugenol (ME) to 1′-sulfooxymethyleugenol (1′HMES) appears to be negligible. Moreover, the PBK model predicted the formation of 1′-sulfooxymethyleugenol (1′HMES) in the liver of human and rat to be linear from doses as high as the benchmark dose (BMD10) down to as low as the virtual safe dose (VSD). This study shows that kinetic data do not provide a reason to argue against linear extrapolation from the rat tumor data to the human situation.

化学物質の健康影響に関する基準値等の設定方法と最近の国際動向

The frame work of chemical risk assessment consists of the four key steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. After the hazard identification step, generally, a threshold approach or a non-threshold approach is selected as a procedure of dose-response assessment, in accordance of genotoxic characterization. Traditionally, default uncertainty factors had been used for TDI(tolerable daily intake) derivation in the threshold approach, and specific mathematical models had been used for low-dose extrapolation, such as VSD (virtually safe dose) derivation, in the non-threshold approach. In order to derive more scientifically rational TDIs or to increase transparency, use of chemical specific adjusting factors (CSAFs) and/or a benchmark dose approach method have been recommended recently by WHO/IPCS for the guidance value derivation. The procedures and current trends of guidance value setting, such as TDIs or VSDs, for human health effects by chemical exposure was summarized in this article.

Assessment of safety/risk vs. Public health concerns: Aflatoxins and hepatocarcinoma.

Hepatocellular carcinoma, (HCC) is a serious health problem. It is prevalent in certain parts of the world where food contamination with aflatoxin is common. Aflatoxin, especially AFB(1), has been shown to induce HCC in many species of laboratory and wild animals, including subhuman primates. Carcinogenesis studies have demonstrated that AFB(1) is a potent genotoxic carcinogen. After bioactivation it may covalently bind with protein and with DNA. The former reaction is positively correlated with AFB(1) exposure, and the latter signifies initiation of the carcinogenesis process.With these biomarkers, epidemiological studies have amply demonstrated the etiological role of aflatoxin in HCC. However, hepatitis B virus also contributes to the development of HCC. Risks and VSD (virtual safe dose) have been estimated from animal and epidemiological studies. These estimates further confirm that AFB(1) is a potent carcinogen. Furthermore, the effects of AFB(1) exposure and hepatitis B are synergistic. Some preventive measures, such as lowering the contamination level of AFB(1) in food and appropriate vaccination programs, have been implemented in many parts of the world. Chemopreventive agents. which may abolish or reduce the effects of AFB(1) are being tested for their effectiveness.

Optimal Designs for Estimating the Percentiles of the Risk in Multistage Models of Carcinogenesis

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Likelihood misspecification and safe dose determination for clustered binary data

Development toxicity experiments are designed to assess potential adverse effects of drugs and other exposures on developing foetuses. Several authors have advocated the use of dose–response models to predict safe exposure levels. Different definitions and approaches leading to a so-called virtually safe dose (VSD) have been introduced. Moreover, a range of parametric dose–response models have been developed. The aim of this paper is to compare a number of VSD estimators and to study the effect of misspecifying the probabilistic model. Attention is restricted to likelihood estimation. The methods are applied to data collected under the National Toxicology Program. The goal of these experiments was to investigate effects in mice of three different chemicals. The outcomes of interest are foetal malformations, classified as being external, visceral and skeletal. © 1997 John Wiley & Sons, Ltd.

Likelihood misspecification and safe dose determination for clustered binary data

Development toxicity experiments are designed to assess potential adverse effects of drugs and other exposures on developing foetuses. Several authors have advocated the use of dose–response models to predict safe exposure levels. Different definitions and approaches leading to a so-called virtually safe dose (VSD) have been introduced. Moreover, a range of parametric dose–response models have been developed. The aim of this paper is to compare a number of VSD estimators and to study the effect of misspecifying the probabilistic model. Attention is restricted to likelihood estimation. The methods are applied to data collected under the National Toxicology Program. The goal of these experiments was to investigate effects in mice of three different chemicals. The outcomes of interest are foetal malformations, classified as being external, visceral and skeletal. © 1997 John Wiley & Sons, Ltd.

Risk Assessment of Inhaled Chloroform Based on Its Mode of Action

The development of scientifically sound risk assessments based on mechanistic data will enable society to better allocate scarce resources. Inadequate risk assessments may result in potentially dangerous levels of hazardous chemicals, whereas overly conservative estimates can result in unnecessary loss of products or industries and waste limited resources. Risk models are used to extrapolate from high-dose rodent studies to estimate potential effects in humans at low environmental exposures and determine a virtually safe dose (VSD). When information to the contrary is not available, the linearized multistage (LMS) model, a conservative model that assumes some risk of cancer at any dose, is traditionally employed. In the case of airborne chloroform, the dose at which an increased lifetime cancer risk of 10(-6) could be calculated was chosen as the target VSD. Applying the LMS model to the mouse liver tumor data from a corn-oil gavage bioassay yields a VSD of 0.000008 ppm chloroform in the air. The weight of evidence indicates that chloroform is not directly mutagenic but, rather, acts through a nongenotoxic-cytotoxic mode of action. In this case, tumor formation results from events secondary to induced cytolethality and regenerative cell proliferation. Toxicity is not observed in rodents when chloroform is not converted to toxic metabolites at a rate sufficient to kill cells. Thus, tumors would not be anticipated at doses that do not induce cytolethality, contrary to the predictions of the LMS model. Inhalation studies in rodents show no cytolethality or regenerative cell proliferation in mouse liver at a chloroform concentration of 10 ppm as the no observed effect level (NOEL) or below. Using that NOEL and a safety factor approach, one can develop a VSD of 0.01 ppm. Integrating these data into the risk assessment process will yield risk estimates that are appropriate to the route of administration and consistent with the mode of action.

Risk Evaluation of Environmental Carcinogens

Risk Evaluation of Environmental Car cinogens: Shigeaki Sato. Department of Hygiene, Kobe University School of Medicine—Quantitative risk evaluation of environmental carcinogens is required not only for their regulation but also for primary cancer prevention. Risk evaluation of carcinogens is carried out through identification of carcinogenicity, exposure assessment, dose‐response assessment, and risk characterization. Exposure assessment is made by measuring the amounts of carcinogens in the environment and their human intake is estimated. Dose‐response assessment is based upon whole‐life carcinogenesis experiments in animals with multiple doses of carcinogens. By downward extrapolation of the dose‐response curve obtained, a virtually safe dose (VSD), i.e., a dose which yields a cancer incidence of 10−6, is calculated and this value is compared with the actual human intake of the carcinogen concerned. When the human intake is around or less than the VSD, that environmental carcinogen is regarded safe to humans because humans as well as experimental animals develop cancer in almost 100% of cases during their whole life and the contribution of a chemical to the occurrence of cancer at an incidence of less than one out of one million is regarded as meaningless. These procedures for risk evaluation of carcinogenic food additives such as butylated hydroxyanisole and saccharin sodium showed that their human intake is one hundredth or much less than the respective VSD values, and this may be the case with most environmental carcinogens except some carcinogenic medical drugs. Human cancer development seems much more influenced by life‐style factors, such as a high‐fat diet or cigarette smoking, and recognition of this fact is crucial for primary cancer prevention.

A 90-Day Chloroform Inhalation Study in Female and Male B6C3F1Mice: Implications for Cancer Risk Assessment

High doses of chloroform induced liver cancer in male and female B6C3F1mice when administered by gavage, kidney cancer in male Osborne–Mendel rats when given by gavage or in the drinking water, and kidney cancer in male BDF1mice when administered by inhalation. The weight of evidence indicates that chloroform is acting through a nongenotoxic–cytotoxic mode of action. The present study was designed to investigate the dose–response relationships for chloroform-induced lesions and regenerative cell proliferation in B6C3F1mice as the basis for formulation of a biologically based risk assessment for inhaled chloroform. Different groups of female and male B6C3F1mice were exposed to atmospheric concentrations of 0, 0.3, 2, 10, 30, and 90 ppm chloroform 6 hr/day, 7 days/week for exposure periods of 4 days or 3, 6, or 13 consecutive weeks. Some additional exposure groups were exposed for 5 days/week for 13 weeks or were exposed for 6 weeks and then examined at 13 weeks. Bromodeoxyuridine was administered via osmotic pumps implanted 3.5 days prior to necropsy, and the labeling index (LI, percentage of nuclei in S-phase) was evaluated immunohistochemically from histological sections. Complete necropsy and microscopic evaluation revealed treatment-induced dose- and time-dependent lesions only in the livers and nasal passages of the female and male mice and in the kidneys of the male mice. Large, sustained increases in the liver LI were seen in the 90-ppm groups at all time points. The female mice were most sensitive, with a no-observed-adverse-effect level (NOAEL) for induced hepatic cell proliferation of 10 ppm. The hepatic LI in the 5 days/week groups were about half of those seen in the 7 days/week groups and had returned to the normal baseline in the 6-week recovery groups. Induced renal histologic changes and regenerative cell proliferation were seen in the male mice at 30 and 90 ppm with 7 days/week exposures and also at 10 ppm with the 5 days/week regimen. Nasal lesions were transient and confined to mice exposed to 10, 30, or 90 ppm for 4 days. In a previous cancer bioassay, a gavage dose of 477 mg/kg/day produced a 95% liver tumor incidence in female B6C3F1mice. This gavage dose is equivalent to a daily 6 hr/day inhalation exposure of approximately 80 ppm, based on the observed induced increases in the LI as an internal dosimeter. The United States Environmental Protection Agency currently uses the linearized multistage model applied to the mouse liver tumor data from the chloroform gavage study to estimate a virtually safe dose (VSD) as a one in a million increased lifetime risk of cancer. The resulting value is an airborne exposure concentration of 0.000008 ppm. Assuming that chloroform-induced female mouse liver cancer is secondary to events associated with necrosis and regenerative cell proliferation, then no increases in liver cancer in female mice would be predicted at the NOAEL of 10 ppm or below based on the results reported here. Applying an uncertainty factor of 1000 yields an estimate of a VSD at 0.01 ppm. This estimate relies on inhalation data and is more consistent with the mode of action of chloroform.

Quantitative risk assessment and the limitations of the linearized multistage model.

1. Quantifying carcinogenic risk is an important objective for assisting in the assessment and management of risks from chemical exposure. The most widely used of the many mathematical models proposed for extrapolation of carcinogenicity data from animal studies to low dose human exposures is the linearized multistage (LMS) model. This has, in effect, become the default approach for much of Quantitative Risk Assessment (QRA). The practical properties of this model have been investigated. 2. Analysis of stimulated data using the LMS model showed (i) that the Maximum Likelihood Estimate (MLE) of the low dose slope, q1, was unstable and extremely sensitive to small changes in the data; (ii) the 95% Upper Confidence Limit (UCL) estimate, q1*, preferred by the US Environmental Protection Agency (EPA) was insensitive with only small changes in values being obtained for large changes in the data; (iii) data sets where there was no statistical significance could give risk estimates similar to those obtained from data sets with clear dose-related effects; (iv) the size of the values of the Virtually Safe Dose (VSD) obtained did not necessarily relate to the biological interpretation of the data sets; (v) the value of q1* obtained was closely related to the top dose used in the study. 3. Limitations of the LMS model were illustrated by examples of its use in assessing the carcinogenicity of 2, 3, 7, 8-TCDD leading to the conclusion that the existing models are not suitable for routine use in the estimation of the risk from chemical carcinogens. The use of the LMS model has been justified in part by its original derivation from a mathematical model based upon a multistage model of carcinogenesis. However, estimates of the parameters of the model used to provide estimates of low dose risk to humans have no direct relationship to specific biological event in carcinogenesis. Further developments in mathematical models and increased understanding of the biological events underlying the carcinogenesis will lead to more biologically plausible QRA methods which would then justify serious consideration of QRA by regulatory authorities throughout the world.

A 90-Day Chloroform Inhalation Study in Female and Male B6C3F1 Mice: Implications for Cancer Risk Assessment

High doses of chloroform induced liver cancer in male and female B6C3F1 mice when administered by gavage, kidney cancer in male Osborne-Mendel rats when given by gavage or in the drinking water, and kidney cancer in male BDF1 mice when administered by inhalation. The weight of evidence indicates that chloroform is acting through a nongenotoxic-cytotoxic mode of action. The present study was designed to investigate the dose-response relationships for chloroform-induced lesions and regenerative cell proliferation in B6C3F1 mice as the basis for formulation of a biologically based risk assessment for inhaled chloroform. Different groups of female and male B6C3F1 mice were exposed to atmospheric concentrations of 0, 0.3, 2, 10, 30, and 90 ppm chloroform 6 hr/day, 7 days/week for exposure periods of 4 days or 3, 6, or 13 consecutive weeks. Some additional exposure groups were exposed for 5 days/week for 13 weeks or were exposed for 6 weeks and then examined at 13 weeks. Bromodeoxyuridine was administered via osmotic pumps implanted 3.5 days prior to necropsy, and the labeling index (LI, percentage of nuclei in S-phase) was evaluated immunohistochemically from histological sections. Complete necropsy and microscopic evaluation revealed treatment-induced dose- and time-dependent lesions only in the livers and nasal passage of the female and male mice and in the kidneys of the male mice. Large, sustained increases in the liver LI were seen in the 90-ppm groups at all time points. The female mice were most sensitive, with a no-observed-adverse-effect level (NOAEL) for induced hepatic cell proliferation of 10 ppm. The hepatic LI in the 5 days/week groups were about half of those seen in the 7 days/week groups and had returned to the normal baseline in the 6-week recovery groups. Induced renal histologic changes and regenerative cell proliferation were seen in the male mice at 30 and 90 ppm with 7 days/week exposures and also at 10 ppm with the 5 days/week regimen. Nasal lesions were transient and confined to mice exposed to 10, 30, or 90 ppm for 4 days. In a previous cancer bioassay, a gavage dose of 477 mg/kg/day produced a 95% liver tumor incidence in female B6C3F1 mice. This gavage dose is equivalent to a daily 6 hr/day inhalation exposure of approximately 80 ppm, based on the observed induced increases in the LI as an internal dosimeter. The United States Environmental Protection Agency currently uses the linearized multistage model applied to the mouse liver tumor data from the chloroform gavage study to estimate a virtually safe dose (VSD) as a one in a million increased lifetime risk of cancer. The resulting value is an airborne exposure concentration of 0.000008 ppm. Assuming that chloroform-induced female mouse liver cancer is secondary to events associated with necrosis and regenerative cell proliferation, then no increases in liver cancer in female mice would be predicted at the NOAEL of 10 ppm or below based on the results reported here. Applying an uncertainty factor of 1000 yields an estimate of a VSD at 0.01 ppm. This estimate relies on inhalation data and is more consistent with the mode of action of chloroform.

The role of regenerative cell proliferation in chloroform-induced cancer

Chloroform produces cancer by a nongenotoxic-cytotoxic mode of action, with no increased cancer risk expected at noncytotoxic doses. The default risk assessment for inhaled chloroform relies on liver tumor incidence from a gavage study with female B6C3F 1 mice and estimates a virtually safe dose (VSD) at an airborne concentration of 0.000008 ppm of chloroform. In contrast, a 1000-fold safety factor applied to the NOAEL for liver cytotoxicity from inhalation studies yields a VSD of 0.01 ppm. This estimate relies on inhalation data and is more consistent with the mode of action of chloroform. Keywords: Chloroform; Nongenotoxic carcinogen; Cell proliferation; Risk assessment

Quick Estimate of the Regulatory Virtually Safe Dose Based on the Maximum Tolerated Dose for Rodent Bioassays

With a limited subset of National Cancer Institute/National Toxicology Program (NCI/NTP) bioassays, Gaylor (Regul. Toxicol. Pharmacol. 9, 101-108, 1989) showed that the regulatory virtually safe dose (VSD), corresponding to an estimated lifetime cancer risk of less than 10−6, could be estimated within a factor of 10 simply by dividing the maximum tolerated dose (MTD), estimated from the results of a 90-day study, by 380,000. The purpose of this current study was to extend the analysis to all carcinogens in the Carcinogenic Potency Database (CPDB) utilizing the TD50 (average daily dose rate in mg/kg body wt/day that was estimated to halve the probability of remaining tumor-free at a specified tissue site throughout a a-year study). Using the relationship between the upper bound on the low-dose slope (q*1) and the TD50 reported by Krewski et al. (Risk. Anal. 13, 383-398, 1993) and the ratio of the maximum dose tested (Max-D)/TD50 obtained in our present analysis, an estimate of the regulatory VSD was given by the MTD/740,000, for NCI/NTP rodent carcinogens. This was about a factor of two lower than the limited analysis conducted by Gaylor. There was little difference when the chemicals were divided into mutagens and nonmutagens. Ninety-six percent (134 of the 139 NCI/NTP rodent carcinogens) of the regulatory VSDs calculated from the individual TD50s obtained from the 2-year bioassays were within a factor of 10 of the MTD/740,000. Gold et al. (Environ. Health Perspect. 79, 259-272, 1989) investigated the distribution of the TD50 among "near-replicate" experiments (where the same chemical was tested more than once and was positive in the same strain, sex, and species by the same route). The distribution of TD50s from near-replicate experiments is similar to the distribution of the Max-D/TD50. Hence, the estimate of the regulatory VSD based on the Max-D/740,000, for NCI/NTP bioassays, is about as precise as the estimate obtained from a 2-year bioassay. This questions the advisability of conducting a 2-year bioassay for purposes of regulatory risk estimation. Since resources are available to test only a small fraction of chemicals to which humans are exposed, a preliminary estimate of the regulatory VSD can be useful in setting testing priorities. If the expected human exposure level is below the regulatory VSD estimated from the MTD, a chemical may be assigned low priority for testing in a 2-year bioassay. Based on previous work the FDA proposed a "threshold of regulation" of a dietary concentration of 0.5 ppb for all substances used in food-contact articles. The results of the present analysis could be used to make the procedure more chemical specific based upon an available MTD. The high correlation between the MTD and estimate of cancer potency (TD50) can be exploited to provide a preliminary, hypothetical upper bound estimate of cancer risk for exposure to a chemical without conducting a 2-year animal bioassay. Thus, the expected level of human exposure relative to the MTD can be used to determine the priority for further research on a chemical, such as mechanistic studies.

Quantitative Risk Assessment of Carcinogenicity of Urethane (Ethyl Carbamatc) on the Basis of Long‐term Oral Administration to B6C3F1 Mice

A carcinogenicity study of urethane was performed for quantitative assessment of Its risk in humans. Three hundred 6‐week‐old male B6C3F1 mice were divided into 6 groups, each consisting of 50 mice, and urethane was given ad libitum in drinking water at levels of 0 (control), 0.6, 3, 6, 60 and 600 ppm for 70 weeks. The tumors with a clear dose‐response relationship were lung tumor (alveolar/ bronchiolar adenoma or carcinoma) and liver tumor (hemangioma or angiosarcoma). The incidences of these two types of tumor were applied to estimation of the virtually safe dose (VSD) at the level of 10 6 by using four mathematical models (Logit, Probit, Weihull and Multistage models). The VSD based on the incidences of lung tumor by using the Logit model was estimated to be 1.8 × 10 4 mg/kg body weight/day. On the other hand the VSD based on those of liver tumor by using the Weibull model was 7.2 × 10−5 mg/kg body weight/day. Thus, the VSDs based on the incidences of the two different types of tumor using the most compatible mathematical model in each case, as judged from the P‐values, were similar.