Iodomethane human health risk characterization

Iodomethane is a new pre-plant soil fumigant approved in the United States. Human exposure may occur via inhalation due to the high vapor pressure of iodomethane. A quantitative human health risk assessment was conducted for inhalation exposure. The critical effects of acute duration iodomethane exposure are: (1) fetal losses in rabbits, (2) lesions in rat nasal epithelium, and (3) transient neurotoxicity in rats. Chronic exposure of rats resulted in increased thyroid follicular cell tumors from sustained perturbation of thyroid hormone homeostasis. A physiologically based pharmacokinetic (PBPK) model for iodomethane was developed to characterize potential human health effects from iodomethane exposure. The model enabled calculation of human equivalent concentrations (HECs) to the animal no-observed-adverse-effect levels (NOAELs) using chemical-specific parameters to determine the internal dose instead of default assumptions. Iodomethane HECs for workers and bystanders were derived using the PBPK model and NOAELs for acute exposure endpoints of concern. The developmental endpoint NOAEL was 10?ppm and corresponding bystander HEC was 7.4?ppm. The nasal endpoint NOAEL was 21?ppm and the HEC was 4.5?ppm. The transient neurotoxicity endpoint NOAEL was 27?ppm and the HEC was10?ppm. Data demonstrated that humans are less sensitive to the effect that causes developmental toxicity in rabbits and the PBPK model incorporated this information, resulting in a higher HEC for the developmental endpoint than for the nasal endpoint. Nasal olfactory degeneration is the primary endpoint for risk assessment of acute exposure to iodomethane.     

A toxicological and dermatological assessment of aryl alkyl alcohols when used as fragrance ingredients

The aryl alkyl alcohol (AAA) fragrance ingredients are a diverse group of chemical structures with similar metabolic and toxicity profiles. The AAA fragrances demonstrate low acute and subchronic dermal and oral toxicity. No carcinogenicity in rats or mice was observed in 2-year chronic testing of benzyl alcohol or α-methylbenzyl alcohol; the latter did induce species and gender-specific renal adenomas in male rats at the high dose. There was no to little genotoxicity, mutagenicity, or clastogenicity in the mutagenic in vitro bacterial assays, and in vitro mammalian cell assays. All in vivo micronucleus assays were negative. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels. At concentrations likely to be encountered by consumers, AAA fragrance ingredients are non-irritating to the skin. The potential for eye irritation is minimal. With the exception of benzyl alcohol and to a lesser extent phenethyl and 2-phenoxyethyl AAA alcohols, human sensitization studies, diagnostic patch tests and human induction studies, indicate that AAA fragrance ingredients generally have no or low sensitization potential. Available data indicate that the potential for photosensitization is low. It is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.     

Subchronic and chronic toxicological investigations on metiram: the lack of a carcinogenic response in rodents.

Metiram complex is a non-systemically acting fungicide of the group of ethylenebisdithiocarbamates (EBDC). The subchronic and chronic toxicity and the carcinogenic potential of metiram (containing 2% ethylene thiourea, ETU, as an intentionally added impurity) were investigated. Doses in the chronic/carcinogenicity rat study were 0, 5, 20, 80, or 320 ppm. In the carcinogenicity study in mice, diets were administered for 89 weeks (females) or 95 weeks (males) at doses of 0, 100, 300, or 1000 ppm. No oncogenic response was noted in either species. The subchronic studies in rats and mice further investigated the thyroid as a target organ. Doses of 0, 5, 80, 320, or 960 ppm were utilized in the rat study and a NOAEL of 80 ppm was established. In the subchronic mouse study, diets containing 0, 300, 1000, 3000, or 7500 ppm were utilized. A NOAEL of 300 ppm was established in this study. In summary, the findings of these studies defined the toxicity of metiram in rodents and demonstrated the lack of a carcinogenic response following chronic dietary exposure in the rat and mouse. The NOAELs that were established in these studies were consistent with the NOAELs established for thyroid toxicity/carcinogenicity in studies on ethylenethiourea (ETU).     

Neurophysiological approaches to the detection of early neurotoxicity in humans

Various neurophysiological methods, including electroencephalography, electromyography, nerve conduction velocities, and evoked potential techniques, have been used to detect early signs of neurotoxicity in humans. These methods have been applied to groups of occupationally exposed workers and their referents in epidemiologic studies, to patients with suspected or proven diseases after long-term work in toxic environment, and to human subjects during or after experimental exposure. The main body of knowledge arises from epidemiologic studies of occupationally exposed subjects, and several chemicals widely used in industry have been shown to be neurotoxic. Of these, e.g., lead causing peripheral neuropathy, some solvents like carbon disulfide, n-hexane, and methyl n-butyl ketone also causing neuropathy and at times central nervous system effects as well as acryl amide have been studied using neurophysiological approaches. Several other solvents including toluene, xylene, and various mixtures of organic solvents have been suspected to be neurotoxic, and nervous system effects have been ascribed to those in several neurophysiological studies. Some studies have elucidated acute nervous system effects of ethyl alcohol or industrial solvents in experimental situations applying, for example, evoked potential techniques or electroencephalography.     

Weight-of-the-evidence review of acrylonitrile reproductive and developmental toxicity studies

Risk assessment of acrylonitrile (AN) toxicity to humans has focused on potential carcinogenicity and acute toxicity. Epidemiological studies from China reported reproductive and developmental effects in AN workers, including infertility, birth defects, and spontaneous abortions. A weight-of-the-evidence (WoE) evaluation of the AN database assessed study strength, characterized toxicity, and identified no-observed-adverse-effect levels (NOAELs). The epidemiological studies do not demonstrate causality and are not sufficiently robust to be used for risk assessment. Rodent developmental studies showed fetotoxicity and malformations at maternally toxic levels; there was no unique developmental susceptibility. NOAELs for oral and inhalation exposures were 10?mg/kg/day and 12?ppm (6?h/day), respectively. Drinking-water and inhalation reproductive toxicity studies showed no clear effects on reproductive performance or fertility. Maternally toxic concentrations caused decreased pup growth. The drinking-water reproductive NOAEL was 100?ppm (moderate confidence due to study limitations). The inhalation exposure reproductive and neonatal toxicity high confidence NOAEL was 45?ppm (first generation 90?ppm) (6?h/day). The inhalation reproductive toxicity study provides the most robust data for risk assessment. Based on the WoE evaluation, AN is not expected to be a developmental or reproductive toxicant in the absence of significant maternal toxicity.     

Route-to-route extrapolation of 1,2-dichloroethane studies from the oral route to inhalation using physiologically based pharmacokinetic models

To help develop a comprehensive, quantitative understanding of the hazards of 1,2-dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) exposure by the inhalation route, the results of existing subchronic studies and an extended one-generation reproductive toxicity (EOGRT) study recently conducted by the oral route in rats were extrapolated using a physiologically based pharmacokinetic (PBPK) model. The no observed adverse effects levels (NOAELs) for the endpoints of neurotoxicity and reproductive/developmental toxicity were the highest tested doses of 169 and 155 mg/kg-day, respectively. These NOAELs were equivalent to continuous exposure of rats to minimums of 76 ppm and 62 ppm EDC, respectively, using total metabolism of EDC as the dose metric that is equivalent in the oral and inhalation scenarios. In contrast, the subchronic study NOAEL of 37.5 mg/kg-day corresponded to continuous inhalation of 4.4 ppm EDC, based on equivalent extrahepatic metabolism. The selection of the internal metric which serves to establish route-to-route equivalency was found to profoundly influence the NOAEL-equivalent inhalation exposure concentration and thus will be a key determinant of inhalation toxicity reference criteria developed on the basis of EDC studies conducted by the oral route.     

Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification

The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255–276, 1978) by Munro et al. (Food Chem Toxicol 34:829–867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43–46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.     

A category approach to predicting the repeated-dose hepatotoxicity of allyl esters

We tested a category approach to predict the hepatotoxic effects of repeated doses of allyl esters using a new database for repeated-dose toxicity. Based on information on hepatotoxic mechanism of allyl acetate, the category was defined as allyl esters that are hydrolyzed to allyl alcohol. Allyl alcohol is readily oxidized to acrolein in the liver, causing hepatotoxicity. Seventeen marketed allyl esters were obtained and grouped into category by identifying or predicting allyl alcohol formation. Allyl esters with a saturated straight alkyl carboxylic acid moiety (allyl acetate, hexanoate and heptanoate as tested species, and allyl butyrate, pentanoate, octanoate, nonanoate and decanoate as untested species) are likely similar in rate of ester hydrolysis, thereby defining subcategory 1. NOAEL and LOAEL for the hepatotoxic effects were estimated at 0.12 and 0.25 mmol/kg/d for the untested species, based on those of allyl acetate. The remaining nine allyl esters with other alkyl or aromatic carboxylic acid moieties were placed in subcategory 2: their hepatotoxicity levels were not predictable due to an unclear match between their degree of structural complexity and rate of hydrolysis. Our results demonstrate the usefulness of the category approach for predicting the hepatotoxicity of untested allyl esters with saturated straight alkyl chains.     

Dose-Response Assessment for Developmental Toxicity: I. Characterization of Database and Determination of No Observed Adverse Effect Levels

Developmental toxicity risk assessment currently relies on theestimation of reference doses (RfD_DT^S) or reference concentrations(RfD_DT^S) based on the use of no observed adverse effect levels(NOAELs) and uncertainty factors. The benchmark dose (BMD) hasbeen proposed as an alternative basis for reference value calculations.A large database of 246 developmental toxicity experiments (SegmentII-type studies) representing 1825 data subsets for variousendpoints was compiled for use in comparing NOAEL and BMD approachesto developmental toxicity risk assessment. This paper describesthe characteristics of the database used and the estimationof NOAELs using several approaches. For each endpoint evaluated,two NOAELs were calculated using the NOSTASOT procedure (Tukeyet al., 1985). The first NOAEL calculation, the QNOAEL, wasbased on a quantal response where a litter was defined as "affected"if one or more fetuses or implants in the litter had the endpointof interest. The second NOAEL calculation, the CNOAEL, was basedon the proportion of fetuses or implants affected within eachlitter and was treated as a continuous response variable. Fifty-sevenpercent of the 246 experiments had at least one endpoint thatshowed a significant trend with dose. A total of 386 data setswere significant with respect to both the quantal and continuoustest of trend. An additional 44 data sets were identified withsignificant trend only by the quantal approach whereas 177 additionaldata sets were identified with significant trend tests onlyby the continuous approach. Thus, the continuous approach appearedto be more powerful in detecting dose-related toxicity, butthe patterns detected by the two approaches differed. QNOAELsand CNOAELs were compared by examining the degree to which theyselected the same dose group. For 98% of the 386 data sets withboth significant continuous and quantal trend tests, the CNOAELwas within one dose level of the QNOAEL. For data sets havingsignificant continuous and/or quantal trend tests, 99% of thetwo NOAELs were within two dose levels. Twenty of the NTP studieswere reviewed for comparison of "expert" versus statisticallyderived NOAELs. Most of the 360 NOAELs derived were identicalfor these two approaches; for the 8% that were different, approximately80% were within one dose level. Thus, the statistically derivedNOAELs that were used as the basis of our data comparisons werereflective of the typical methods used in deriving NOAELs. Compilationand characterization of such a large database of Segment IIdevelopmental toxicity experiments provide us with an opportunityto evaluate new quantitative approaches for developmental toxicityrisk assessment and to make decisions about appropriate approachesfor evaluation.     

Development of a physiologically based pharmacokinetic (PBPK) model for methyl iodide in rats,rabbits, and humans

Methyl iodide (MeI) has been proposed as an alternative to methyl bromide as a pre-plant soil fumigant that does not deplete stratospheric ozone. In inhalation toxicity studies performed in animals as part of the registration process, three effects have been identified that warrant consideration in developing toxicity reference values for human risk assessment: nasal lesions (rat), acute neurotoxicity (rat), and fetal loss (rabbit). Uncertainties in the risk assessment can be reduced by using an internal measure of target tissue dose that is linked to the likely mode of action (MOA) for the toxicity of MeI, rather than the external exposure concentration. Physiologically based pharmacokinetic (PBPK) models have been developed for MeI and used to reduce uncertainties in the risk assessment extrapolations (e.g. interspecies, high to low dose, exposure scenario). PBPK model-derived human equivalent concentrations comparable to the animal study NOAELs (no observed adverse effect levels) for the endpoints of interest were developed for a 1-day, 24-hr exposure of bystanders or 8?hr/day exposure of workers. Variability analyses of the PBPK models support application of uncertainty factors (UF) of approximately 2 for intrahuman pharmacokinetic variability for the nasal effects and acute neurotoxicity.     

Clinical and toxicological investigations of a case of delayed neuropathy in man after acute poisoning by an organophosphorus pesticide

Progressive neuropathy developed in a man during 2–8 weeks after acute poisoning by a pesticide said to contain trichlorphon. The neuropathy was typical of that caused by organophosphorus esters in the delay and in the maintenance of normal conduction velocity in surviving nerve fibres. A sample alleged to be typical of the ingested material was not more active against hen brain neurotoxic esterase (NTE) than was pure trichlorphon. Delayed neuropathy has never been produced in hens by a single dose of trichlorphon. This incident and studies of human brain in vitro suggest that the ratio neurotoxicity/lethality for trichlorphon is higher in man than in the hen. Suggestion is made of laboratory tests to improve neurotoxicity screening.     

Late acute,delayed neurotoxic and cholinergic effects of S,S,S-tributyl phosphorotrithioite (merphos) in hens

This study reports three toxicologic effects of S,S,S-tributyl phosphorotrithioite (merphos) in hens: acute cholinergic, late acute, or delayed neurotoxic. These effects can be differentiated by route of administration, dosage required, severity and reversibility of clinical signs, and production of pathologic lesions of the nervous system. Oral administration of a single dose (200 to 2000 mg/kg) of merphos caused weak cholinergic effects, which were rapidly relieved by atropine sulfate treatment. Four days after start of administration of large daily doses (80 mg/kg/day) a late acute effect was observed. The clinical signs of the late acute effects were identical to those produced by n-butyl mercaptan (nBM), a hydrolytic product of merphos, and were not relieved by atropine sulfate. The late acute effect overlapped with the clinical signs of delayed neurotoxicity. Late acute toxicity was not seen with topical application of single or daily doses of merphos; rather, delayed neurotoxicity was consistently produced. Degeneration of the anterior columns in the spinal cord was identical to that found in tri-o-cresyl phosphate-treated hens and was the most consistent histopathologic change. Topical administration of merphos caused a more prolonged inhibition of plasma butyrylcholinesterase activity than the orally administered compound. Orally administered merphos was rapidly metabolized in the gastrointestinal tract directly to nBM or following its oxidation to S,S,S-tributyl phosphorotrithioate. nBM apparently caused the late acute toxic effect. Topically administered merphos, which was not metabolized in the gastrointestinal tract, caused delayed neurotoxicity but did not produce a late acute effect. The present results demonstrate that evaluation of the neurotoxic effect of organophosphorus esters should include investigation with both oral and topical application.     

A retrospective analysis of toxicity studies in dogs and impact on the chronic reference dose for conventional pesticide chemicals

Prior to October 2007, the US Environmental Protection Agency (EPA) required both 13-week and 1-year studies in Beagle dogs be submitted in support of registration for pesticides. Following an extensive retrospective analysis, we (the authors) determined that the 1-year toxicity dog study should be eliminated as a requirement for pesticide registration. The present work presents this retrospective analysis of results from 13-week and 1-year dog studies for 110 conventional pesticide chemicals, representing more than 50 classes of pesticides. The data were evaluated to determine if the 13-week dog study, in addition to the long-term studies in two rodent species (mice and rats), were sufficient for the identification of no observed adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) for the derivation of chronic reference doses (RfD). Only pesticides with adequate 13-week and 1-year duration studies were included in the present evaluation. Toxicity endpoints and dose-response data from 13-week and 1-year studies were compared. The analysis showed that 70 of the 110 pesticides had similar critical effects regardless of duration and had NOAELs and LOAELs within a difference of 1.5-fold of each other. For the remaining 40 pesticides, 31 had lower NOAELs and LOAELs in the 1-year study, primarily due to dose selection and spacing. In only 2% of the cases were additional toxic effects identified in the 1-year study that were not observed in the 13-week study and/or in the rodent studies. In 8% of the cases, the 1-year dog had a lower NOAEL and/or LOAEL than the 13-week study, but there would have been no regulatory impact if the 1-year dog study had not been performed because adequate data were available from the other required studies. A dog toxicity study beyond 13-weeks does not have significant impact on the derivation of a chronic RfD for pesticide risk assessment.     

Is current risk assessment of non-genotoxic carcinogens protective?

Non-genotoxic carcinogens (NGTXCs) do not cause direct DNA damage but induce cancer via other mechanisms. In risk assessment of chemicals and pharmaceuticals, carcinogenic risks are determined using carcinogenicity studies in rodents. With the aim to reduce animal testing, REACH legislation states that carcinogenicity studies are only allowed when specific concerns are present; risk assessment of compounds that are potentially carcinogenic by a non-genotoxic mode of action is usually based on subchronic toxicity studies. Health-based guidance values (HBGVs) of NGTXCs may therefore be based on data from carcinogenicity or subchronic toxicity studies depending on the legal framework that applies. HBGVs are usually derived from No-Observed-Adverse-Effect-Levels (NOAELs). Here, we investigate whether current risk assessment of NGTXCs based on NOAELs is protective against cancer. To answer this question, we estimated Benchmark doses (BMDs) for carcinogenicity data of 44 known NGTXCs. These BMDs were compared to the NOAELs derived from the same carcinogenicity studies, as well as to the NOAELs derived from the associated subchronic studies. The results lead to two main conclusions. First, a NOAEL derived from a subchronic study is similar to a NOAEL based on cancer effects from a carcinogenicity study, supporting the current practice in REACH. Second, both the subchronic and cancer NOAELs are, on average, associated with a cancer risk of around 1% in rodents. This implies that for those chemicals that are potentially carcinogenic in humans, current risk assessment of NGTXCs may not be completely protective against cancer. Our results call for a broader discussion within the scientific community, followed by discussions among risk assessors, policy makers, and other stakeholders as to whether or not the potential cancer risk levels that appear to be associated with currently derived HBGVs of NGXTCs are acceptable.     

Barium: rationale for a new oral reference dose.

The U.S. Environmental Protection Agency (EPA) has an established oral reference dose (RfD) value for Ba of 0.07 mg Ba/kg/d based on a 1984 investigation that reported hypertension. In this study, the toxicological data for Ba has been reevaluated and a revised oral RfD is proposed. The toxicokinetic, acute, and chronic toxicity, carcinogenicity, and reproductive animal studies as well as epidemiological and occupational health human studies for Ba exposure were reviewed for applicability to an oral RfD. The available human studies have some utility but suffer from either a small population size, a short exposure regimen, or difficulties in identifying definitive Ba exposure in the study population. As a result, the available long-term animal studies were found to be more appropriate for the RfD derivation. A dose-response assessment of no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values determined that kidney effects are the most sensitive endpoint for adverse health effects related to chronic soluble Ba ingestion in mammals. The most complete animal studies were conducted by the National Toxicology Program (NTP, 1994) and the lowest species NOAELs were 75 mg Ba/kg/d in male mice and 60 mg Ba/kg/d for male rats. The male rats were identified to be the most sensitive population tested and their NOAEL value was selected for extrapolation to an oral RfD. Application of overall uncertainty factors to the lowest NOAEL value from a chronic animal study of either 90 (based on an approach proposed by Dourson, 1994) or the generally accepted 100 results in an oral RfD of 0.66 mg Ba/kg/d or 0.6 mg Ba/kg/d, respectively. It is proposed to use the more conservative value of 0.6 mg Ba/kg/d. This reassessment results in nearly an order of magnitude increase in the U.S. EPA oral RfD for Ba.     

BARIUM: RATIONALE FOR A NEW ORAL REFERENCE DOSE

The U.S. Environmental Protection Agency (EPA) has an established oral reference dose (RfD) value for Ba of 0.07 mg Ba/kg/d based on a 1984 investigation that reported hypertension. In this study, the toxicological data for Ba has been reevaluated and a revised oral RfD is proposed. The toxicokinetic, acute, and chronic toxicity, carcinogenicity, and reproductive animal studies as well as epidemiological and occupational health human studies for Ba exposure were reviewed for applicability to an oral RfD. The available human studies have some utility but suffer from either a small population size, a short exposure regimen, or difficulties in identifying definitive Ba exposure in the study population. As a result, the available long-term animal studies were found to be more appropriate for the RfD derivation. A dose-response assessment of no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values determined that kidney effects are the most sensitive endpoint for adverse health effects related to chronic soluble Ba ingestion in mammals. The most complete animal studies were conducted by the National Toxicology Program (NTP, 1994) and the lowest species NOAELs were 75 mg Ba/kg/d in male mice and 60 mg Ba/kg/d or male rats. The male rats were identified to be the most sensitive population tested and their NOAEL value was selected for extrapolation to an oral RfD. Application of overall uncertainty factors to the lowest NOAEL value from a chronic animal study of either 90 (based on an approach proposed by Dourson, 1994) or the generally accepted 100 results in an oral RfD of 0.66 mg Ba/kg/d or 0.6 mg Ba/kg/d, respectively. It is proposed to use the more conservative value of 0.6 mg Ba/kg/d. This reassessment results in nearly an order of magnitude increase in the U.S. EPA oral RfD for Ba.     

Human health risk assessment of chloroxylenol in liquid hand soap and dishwashing soap used by consumers and health-care professionals

A quantitative human risk assessment of chloroxylenol was conducted for liquid hand and dishwashing soap products used by consumers and health-care workers. The toxicological data for chloroxylenol indicate lack of genotoxicity, no evidence of carcinogenicity, and minimal systemic toxicity. No observed adverse effect levels (NOAEL) were established from chronic toxicity studies, specifically a carcinogenicity study that found no cancer excess (18 mg/kg-day) and studies of developmental and reproductive toxicity (100 mg/kg-day). Exposure to chloroxylenol for adults and children was estimated for two types of rinse-off cleaning products, one liquid hand soap, and two dishwashing products. The identified NOAELs were used together with exposure estimates to derive margin of exposure (MOE) estimates for chloroxylenol (i.e., estimates of exposure over NOAELs). These estimates were designed with conservative assumptions and likely overestimate exposure and risk (i.e., highest frequency, 100% dermal penetration). The resulting MOEs ranged from 178 to over 100, 000, 000 indicating negligibly small potential for harm related to consumer or health-care worker exposure to chloroxylenol in liquid soaps used in dish washing and hand washing.     

Evaluation of acute inhalation toxicity for chemicals with limited toxicity information

A large reference database consisting of acute inhalation no-observed-adverse-effect levels (NOAELs) and acute lethality data for 97 chemicals was compiled to investigate two methods to derive health-protective concentrations for chemicals with limited toxicity data for the evaluation of one-hour intermittent inhalation exposure. One method is to determine threshold of concern (TOC) concentrations for acute toxicity potency categories and the other is to determine NOAEL-to-LC(50) ratios. In the TOC approach, 97 chemicals were classified based on the Globally Harmonized System of Classification and Labeling of Chemicals proposed by the United Nations into different acute toxicity categories (from most toxic to least toxic): Category 1, Category 2, Category 3, Category 4, and Category 5. The tenth percentile of the cumulative percentage distribution of NOAELs in each category was determined and divided by an uncertainty factor of 100 to derive the following health-protective TOC concentrations: 4microg/m(3) for chemicals classified in Category 1; 20microg/m(3) for Category 2; 125microg/m(3) for both Categories 3 and 4; and 1000microg/m(3) for Category 5. For the NOAEL-to-LC(50) ratio approach, 55 chemicals with NOAEL exposure durations < or = 24 hour were used to calculate NOAEL-to-LC(50) ratios. The tenth percentile of the cumulative percentage distribution of the ratios was calculated and divided by an uncertainty factor of 100 to produce a composite factor equal to 8.3x10(-5). For a chemical with limited toxicity information, this composite factor is multiplied by a 4-hour LC(50) value or other appropriate acute lethality data. Both approaches can be used to produce an estimate of a conservative threshold air concentration below which no appreciable risk to the general population would be expected to occur after a one-hour intermittent exposure.     

A comparison of ratio distributions based on the NOAEL and the benchmark approach for subchronic-to-chronic extrapolation.

One approach to derive a data-based assessment factor (AF) for subchronic-to-chronic extrapolation is to determine ratios between the NOAEL(subchronic) and NOAEL(chronic) for the same compounds. Instead of using ratios of NOAELs, the distribution can also be estimated by ratios of subchronic and chronic Benchmark Doses (or Critical Effect Doses, CEDs, for continuous data). In this study 314 dose-response datasets on body weights and liver weights of mice and rats were selected providing dose-response information after both subchronic and chronic exposure. NOAEL ratios could be derived in only 68 of these datasets, while CED ratios could be derived in 189 datasets. When only the (53) datasets suitable for both approaches were evaluated the variation of the CED ratio distribution (GSD [geometric standard deviation]: 2.9) was smaller than the one of the NOAEL ratio distribution (GSD: 3.3). After correcting for the estimation error of the individual CED ratios the GSD of the CED distribution decreased to 2.3. The geometric means (GMs) of the NOAEL and CED distributions were similar (1.2 and 1.6, respectively). Comparing the NOAEL distribution based on all 68 datasets suitable for deriving NOAEL ratios with the CED distribution based on the 189 ratios suitable for deriving CED ratios resulted in similar GMs (1.5 and 1.7, respectively), but the GSDs differed considerably (5.3 and 2.3 respectively). It is concluded that usage of the CED approach results in less wide distributions. Furthermore, a larger fraction of available datasets is useful to inform the ratio distribution. This results in more accurate, and less conservative distributions of AFs in general compared to the distributions based on NOAEL ratios that have been proposed so far.     

The Use of Benchmark Dose Methodology with Acute Inhalation Lethality Data

Benchmark dose methodology has been proposed as a refinement to the no observed adverse effect level (NOAEL) methods currently used for health risk assessments. We compared log-normal probit and quantal Weibull benchmark concentration (BMC) estimates using 1, 5, and 10% response incidences with inhalation toxicity NOAELs and LOAELs from 120 acute lethality data sets. These studies yielded relatively steep dose-response slopes, which in turn influenced the suitability of selecting response incidences. The mean magnitude of difference between the 95% lower confidence limits (LCLs) for 1, 5, or 10% BMCs and corresponding NOAELs was less than twofold using the probit model and less than fourfold using the Weibull model. BMC estimates at the 10% response exceeded the observed LOAEL in some cases. Maximum likelihood estimates for doses with 1, 5, or 10% responses frequently exceeded LOAELs. The probit model repeatedly gave a better fit for the data compared with the Weibull model, resulting in improved goodness of fit tests and reduced 95% confidence intervals. The 95% LCL appears to be necessary at the 1, 5, or 10% response levels in order to safely estimate a concentration below that resulting in a LOAEL.