Intraspecies Extrapolation Research Articles

Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits.

This work aimed at improving the empirical database of time (i.e., exposure duration), interspecies and intraspecies extrapolation when deriving occupational exposure limits (OELs). For each extrapolation step, a distribution was derived, which can be used to model the associated uncertainties. For time and interspecies extrapolation, distributions of ratios of dose descriptors were derived from studies of different length or species. National Toxicology Program (NTP) study data were manually assessed, and data from REACH (Registration, Evaluation and Authorisation of Chemicals) registration dossiers were evaluated semi‐automatically. Intraspecies extrapolation was investigated by compiling published studies on human toxicokinetic and toxicodynamic variability. A new database was established for toxicokinetic differences in interindividual susceptibility, including many inhalation studies. Using NTP data produced more reliable results than using REACH data. The geometric mean (GM) for time extrapolation subacute/chronic agreed with previous evaluations (GM = 4.11), whereas the GM for subchronic/chronic extrapolation was slightly higher (GM = 2.93) than the GMs found by others. No significant differences were observed between systemically and locally acting substances. Observed interspecies differences confirmed the suitability of allometric scaling, with the derived distribution describing remaining uncertainty. Distributions of intraspecies variability at the 1% and 5% incidence level had medians of 7.25 and 3.56, respectively. When compared with assessment factors (AFs) currently used in the EU, probabilities that these AFs are protective enough span a wide range from 10% to 95%, depending on the extrapolation step. These results help to select AFs in a transparent and informed way and, by allowing to compare protection levels achieved, to harmonise methods for deriving OELs.

Derivation of occupational exposure limits: Differences in methods and protection levels.

Frameworks for deriving occupational exposure limits (OELs) and OEL‐analogue values (such as derived‐no‐effect levels [DNELs]) in various regulatory areas in the EU and at national level in Germany were analysed. Reasons for differences between frameworks and possible means of improving transparency and harmonisation were identified. Differences between assessment factors used for deriving exposure limits proved to be one important reason for diverging numerical values. Distributions for exposure time, interspecies and intraspecies extrapolation were combined by probabilistic methods and compared with default values of assessment factors used in the various OEL frameworks in order to investigate protection levels. In a subchronic inhalation study showing local effects in the respiratory tract, the probability that assessment factors were sufficiently high to protect 99% and 95% of the target population (workers) from adverse effects varied considerably from 9% to 71% and 17% to 87%, respectively, between the frameworks. All steps of the derivation process, including the uncertainty associated with the point of departure (POD), were further analysed with two examples of full probabilistic assessments. It is proposed that benchmark modelling should be the method of choice for deriving PODs and that all OEL frameworks should provide detailed guidance documents and clearly define their protection goals by stating the proportion of the exposed population the OEL aims to cover and the probability with which they intend to provide protection from adverse effects. Harmonisation can be achieved by agreeing on the way to perform the methodological steps for deriving OELs and on common protection goals.

Quantitative human health risk assessment along the lifecycle of nano-scale copper-based wood preservatives

The use of nano-scale copper oxide (CuO) and basic copper carbonate (Cu2(OH)2CO3) in both ionic and micronized wood preservatives has raised concerns about the potential of these substances to cause adverse humans health effects. To address these concerns, we performed quantitative (probabilistic) human health risk assessment (HHRA) along the lifecycles of these formulations used in antibacterial and antifungal wood coatings and impregnations by means of the EU FP7 SUN project’s Decision Support System (SUNDS, www.sunds.gd). The results from the risk analysis revealed inhalation risks from CuO in exposure scenarios involving workers handling dry powders and performing sanding operations as well as potential ingestion risks for children exposed to nano Cu2(OH)2CO3 in a scenario involving hand-to-mouth transfer of the substance released from impregnated wood. There are, however, substantial uncertainties in these results, so some of the identified risks may stem from the safety margin of extrapolation to fill data gaps and might be resolved by additional testing. Our stochastic approach successfully communicated the contribution of different sources of uncertainty in the risk assessment. The main source of uncertainty was the extrapolation from short to long-term exposure, which was necessary due to the lack of (sub)chronic in vivo studies with CuO and Cu2(OH)2CO3. Considerable uncertainties also stemmed from the use of default inter- and intra-species extrapolation factors.

Toxicokinetic and toxicodynamic considerations when deriving health-based exposure limits for pharmaceuticals

The purpose of this paper is to describe the use of toxicokinetic (TK) and toxicodynamic (TD) data in setting acceptable daily exposure (ADE) values and occupational exposure limits (OELs). Use of TK data can provide a more robust exposure limit based on a rigorous evaluation of systemic internal dose. Bioavailability data assist in extrapolating across different routes of exposure to be protective for route-based differences of exposure. Bioaccumulation data enable extrapolation to chronic exposures when the point of departure (PoD) is from a short-term critical study. Applied in the context of chemical-specific adjustment factors (CSAFs), TK data partially replace traditional default adjustment factors for interspecies extrapolation (extrapolation from studies conducted in animals to humans) and intraspecies variability (to account for human population variability). Default adjustments of 10-fold each for interspecies and intraspecies extrapolation are recommended in several guidelines, although some organization recommend other values. Such default factors may overestimate variability for many APIs, while not being sufficiently protective for variability with other APIs. For this reason, the use of chemical specific TK and TD data are preferred. Making full use of existing TK and TD data reduces underlying uncertainties, increases transparency, and ensures that resulting ADEs reflect the best available science.

Richtwerte für 2-Ethylhexanol in der Innenraumluft

The German Ad-hoc Working Group on Indoor Guidelines of the Indoor Air Hygiene Committee and of the Supreme State Health Authorities is issuing indoor air guide values to protect public health. 2-Ethylhexan-1-ol (EH) is used amongst others as an intermediate in the production of plasticisers or as a flavouring agent in food, cosmetics and cleaning agents. EH is detectable in nearly all indoor air samples. Indoor air concentrations in Germany were reported to be in the range of 0.002 to 0.006 mg/m3 (median), the 95-percentiles were in the range of 0.009 to 0.03 mg/m3. Toxicity after acute exposure to EH is low. EH is irritating to skin and eyes after direct contact. Acute exposure of humans to 54 mg EH/m3 caused sensory irritation (NOAEC 8 mg EH/m3). In a subchronic inhalation study in rats, neither local nor systemic effects were detectable up to the highest concentration tested (638 mg/m3). EH is not genotoxic and not carcinogenic in rats and male mice after oral application. There is no evidence that EH impairs fertility. Developmental toxicity was only observed at doses, which already caused maternal toxicity (650 mg/kg bw/d). Sensory irritation is the most relevant effect for the derivation of indoor air guide values. Based on a LOAEC of 54 mg/m3 and a NOAEC of 8 mg/m3 in a short time (4 h) inhalation study with volunteers, and applying an intraspecies extrapolation factor of 10 and a factor of 6 for time extrapolation, a preliminary hazard-based guide value of 1 mg EH/m3 and a preliminary precautionary value of 0.1 mg EH/m3 have been derived.

Refined hazard characterization of 3‐MCPD using benchmark dose modeling

Abstract3‐Monochloropropane‐1,2‐diol (3‐MCPD)‐esters represent a newly identified class of food‐borne process contaminants of possible health concern. Due to hydrolysis 3‐MCPD esters constitute a potentially significant source of free 3‐MCPD exposure and their preliminary risk assessment was based on toxicological data on free 3‐MCPD. 3‐MCPD is a non‐genotoxic carcinogen and a (provisional maximum) tolerable daily intake ((PM)TDI) of 2 µg/kg bodyweight per day was established by the Scientific Committee on Food and the Joint FAO/WHO Expert Committee on Food Additives. Both committees derived the TDI from a lowest observed adverse effect level, not a no observed adverse effect level, for renal tubular hyperplasia, using an uncertainty factor of 500. When using the Benchmark Dose (BMD) approach and a BMDL10 value as point of departure, part of this uncertainty factor of 500 would no longer be needed. The present study presents a BMD analysis of the currently available chronic data on 3‐MCPD mediated induction of tubular hyperplasia in rats as the most sensitive endpoint. The results indicate a (model‐averaged) BMDL10 value of 0.72 mg/kg bw/day. The TDI that would be derived based on this BMDL10 value will depend on the uncertainty factor chosen. Using the default uncertainty factor of 100 for inter‐ and intraspecies extrapolation would result in a TDI of 7 µg/kg bw/day.See commentary by Abraham et al. [p. 1225–1226]

Interspecies Scaling in Pharmacokinetics: A Novel Whole-Body Physiologically Based Modeling Framework to Discover Drug Biodistribution Mechanisms in vivo

Drug approval processes require extensive testing and have recently put more emphasis on understanding mechanistic drug action in the body including toxicity and safety.1 Consequently, there is an urgent need in the pharmaceutical industry to develop mechanistic pharmacokinetic (PK) models able to both expedite knowledge gain from experimental trials and, simultaneously, address safety concerns. We previously developed a first principles based whole-body PK model, which incorporated physiological dimensions and drug mass transport. In this follow-up article, we demonstrate how the first principles model in combination with novel physiological scaling laws yields more reliable interspecies and intraspecies extrapolation of drug biodistribution. We show how experimental dose-response data in rats for immunosuppressant cyclosporin are sufficient for predicting the biodistribution of this drug in pigs, monkeys, and humans. The predicted drug concentrations extrapolated by interspecies scaling laws match well with the experimental measurements. These promising results demonstrate that the whole-body PK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool.

Assessment of margin of exposure based on biomarkers in blood: An exploratory analysis

In chemical risk assessment, exposures in humans are often compared to no-observed-adverse-effect levels or benchmark doses for sensitive adverse responses (“points of departure”) in laboratory species to assess whether a sufficient “margin of exposure” (MOE) is attained to ensure safety. Conventionally, the default target MOE based on external dose is drawn from uncertainty factors of 10 each for inter- and intra-species extrapolation. The increasing availability of blood-based biomonitoring data in humans as well as measured and modeled blood concentrations in laboratory animals in key studies underlying chemical risk assessments may allow assessments of MOE to be made by comparing blood concentrations of parent compound in humans compared to those in the laboratory species at the point of departure for the risk assessment. This exploratory analysis provides an initial evaluation of whether the default MOE of 100 typically applied on an external dose basis is protective when applied on the basis of comparison of blood concentrations between laboratory animals and humans. The evaluation is conducted using a generic physiologically-based pharmacokinetic model of the structure typically applied to volatile organic compounds. Additional considerations relative to other classes of compounds are also addressed. Based on this evaluation, for chemicals with characteristics consistent with the modeling conducted here under certain conditions, the default MOE of 100 is more protective when applied to comparative blood concentrations than when applied on an external dose basis. Depending upon the chemical characteristics, the toxicokinetic components of the inter- and/or intra-species uncertainty factor could be reduced or eliminated when inter- and intra-species comparisons and extrapolations are made based on blood concentrations of parent compound of interest.

A probabilistic effect assessment model for hazardous substances at the workplace

A major problem in risk assessment is the quantification of uncertainties. A probabilistic model was developed to consider uncertainties in the effect assessment of hazardous substances at the workplace. Distributions for extrapolation factors (time extrapolation, inter- and intraspecies extrapolation) were determined on the basis of appropriate empirical data. Together with the distribution for the benchmark dose obtained from substance-specific dose–response modelling for the exemplary substances 2,4,4-trimethylpentene (TMP) and aniline, they represent the input distributions for probabilistic modelling. These distributions were combined by Monte Carlo simulation. The resulting target distribution describes the probability that an aspired protection level for workers is achieved at a certain dose and the uncertainty associated with the assessment. In the case of aniline, substance-specific data on differences in susceptibility (between species; among humans due to genetic polymorphisms of N-acetyltransferase) were integrated in the model. Medians of the obtained target distributions of the basic models for TMP and aniline, but not of the specific aniline model are similar to deterministically derived reference values. Differences of more than one order of magnitude between the medians and the 5th percentile of the target distributions indicate substantial uncertainty associated with the effect assessment of these substances. The probabilistic effect assessment model proves to be a practical tool to integrate quantitative information on uncertainty and variability in hazard characterisation.

Managing uncertainty in health risk assessment

The process of risk (safety) assessment used to determine negligible-risk levels of human exposure to toxicants is subject to a number of sources of uncertainty. In addition to the common uncertainties related to high-to-low-dose extrapolation, interspecies extrapolation and intraspecies extrapolation, there can be uncertainty associated with extrapolation to alternative routes and durations of exposure. Sampling variation is an important source of uncertainty. It is essential that the various sources of uncertainty be taken into account in the risk and exposure extrapolations, but the total uncertainty should be managed in such a way as to avoid setting overly conservative safe exposures. This article discusses a unifying benchmark-dose approach to risk assessment for carcinogenic and noncarcinogenic health effects, and describes a formal quantitative procedure for managing uncertainty that is less conservative than the common practice of reducing a point of departure on a dose-response curve by a product of uncertainty factors to achieve a safe level of exposure.

Life cycle impact assessment of pesticides on human health and ecosystems

The development of methodologies to assess the effects of pesticides in a consistent way and to enable comparison with the impacts from other agricultural practices is urgently needed. This paper describes a life cycle assessment method to determine the impact of pesticides on human health and ecosystems. The approach considers a full-fate analysis and the exposure to toxic pollutants through different media and pathways, including residues in food, based on the behavior of the pesticides in air and the importance of transfers between soil and surface or ground waters. For human toxicity, estimates of pesticide residues show that food intake results in the highest toxic exposure, about 10 3 to 10 5 times higher than that induced by drinking water or inhalation. Better evaluation practices of pesticide residues in food need to be established in priority. For the “no effect concentration (NEC)” used as a reference for both terrestrial and aquatic ecotoxicity, extrapolation methods are developed on the basis of experimental data. Extrapolation coefficients for risk assessment are to be used with caution; an intra-species extrapolation factor of 10 explained the relationship between acute (LC 50) and chronic (NOEC) ecotoxicity, whereas it was not suitable for inter-species extrapolation. The method is applied to a case study of five fungicides that have the same function on wheat. Results obtained for the 100 most commonly used pesticides in Switzerland are presented. It is demonstrated that the comparison of pesticides is feasible, the pollution sources of highest concern being identifiable and the best environmental management practices thereby promoted without penalizing the crop itself.

Intra-Species Extrapolation in Risk Assessment of Different Classes of Antimicrobials

The risk assessment process for non-carcinogens incorporates all available scientific information, including toxicokinetic and toxicodynamic data. A 10-fold uncertainty factor (UF) is most commonly used to account for underlying variability within the human species. The purposes of this investigation are to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharma-codynamic data are incorporated to characterize interindividual variability and whether another UF is needed for the children group. An extensive literature search was conducted on seven antimicrobials in order to incorporate information on kinetics and dynamics to allow extrapolation among susceptible humans. The drugs are cefaclor, cefuroxime, erythromycin, clarithromycin, ampicillin, gentamicin and amikacin. The composite factor was calculated using the highest ratio for appropriate parameters and default subfactor. According to the data, we concluded that when relevant kinetic and dynamic data are available, replacing the default factors with actual data-derived values was possible for the antimicrobials evaluated and that there is no need to add another UF to the children group.

Inter- and Intra-Species Extrapolation in Risk Assessment of Different Classes of Pesticides

Risk assessors routinely use the reference dose (RfD) approach for non-cancer risk assessment. In this approach, No-Observed-Adverse-Effect-Level (NOAEL) is divided by the product of uncertainty factors (UFs) and, occasionally, an additional modifying factor (MF), each usually employed by default as factors of 10. In the present investigation, kinetic and dynamic data have been used in order to reduce uncertainties when establishing exposure guidelines for examples of chemicals representing four classes of pesticides (warfarin, lindane, carbaryl and parathion). An intensive search of databases was conducted for these pesticides, and toxicokinetic and toxicodynamic parameters in inter- and intra-species were evaluated. The kinetic and dynamic subfactors were less than the proposed values of Renwick and the International Programme on Chemical Safety (IPCS). The composite factors for all the examined pesticides were less than 100. The present study indicated that in setting exposure levels it is important to incorporate kinetic and dynamic data, as they become available, rather than rely on default uncertainty factors, which are imprecise in many cases.

Deriving Toxicity Values for Organophosphate Nerve Agents: A Position Paper in Support of the Procedures and Rationale for Deriving Oral RfDs for Chemical Warfare Nerve Agents

During the process of deriving oral Reference Dose (RfDs) values for chemical warfare agents, several issues arose regarding the identification of adverse effect levels and the application of uncertainty factors. For those agents that function as cholinesterase inhibitors (e.g., agents VX, GA, GB, and GD), these issues included the following: (1) Is the endpoint of blood cholinesterase inhibition an indicator of toxicity or a biomarker of exposure? (2) Can an experimental animal species be more sensitive than humans, thereby eliminating the need for an animal-to-human uncertainty factor? (3) Can the uncertainty factor that is used to extrapolate from a lowest-observed adverse-effect-level (LOAEL) to a no-observed-adverse-effect-level (NOAEL) be less than the default value of 10? (4) Can an oral RfD be derived from non-oral toxicity data? (5) Can an uncertainty factor of less than 10 be used to extrapolate from subchronic to chronic exposure (e.g., is the critical effect adequately described by the subchronic exposure data)? (6) What constitutes an adequate data base for organophosphate cholinesterase inhibitors, and what uncertainty factor should be used for an incomplete data base? Analysis of relevant data resulted in the following selection and justifications of uncertainty factors. For uncertainty associated with intraspecies extrapolation (UFH), physiologic and pathologic conditions affecting cholinest-erase activity levels justified maintaining a UFH of 10 for all of the nerve agents. Because available data indicated that humans tended to be more sensitive than rats regarding anticholinesterase effects, an interspecies variability (UFA) factor of 10 was retained for agents GA, GB, and GD. For agent VX, however, the available data revealed that the domestic sheep test species exhibited sensitivity equivalent to or greater than that of humans thereby justifying a UFA of 1. For uncertainties regarding extrapolation from subchronic-to- chronic exposure data, consideration of information on the physiology of cholinergic systems and the available toxicity data for the nerve agents and other cholinest-erase inhibitors indicated that a UFS of 3 was justified for all four of the nerve agents. For uncertainties regarding LOAEL-to- NOAEL extrapolation (UFL), the selection of agent GB, GD, and VX doses resulting in cholinesterase inhibition in the absence of clinical signs of toxicity (biomarker of exposure) justified this endpoint as a minimal LOAEL and a UFL of 3. For agent GA, a NOAEL was used, and therefore no UFL was required. The uncertainty factor for data base completeness (UFD), was based upon several considerations. Of primary concern was the fact that chronic toxicity studies are not considered an essential component of the data base requirements for cholinesterase inhibitors because of the unlikelihood that the endpoint will change with an increase in exposure time beyond that defined as a subchronic exposure. Additionally, limited data regarding reproductive and developmental toxicity were not considered to represent critical toxicity endpoints for the nerve agents or cholinesterase inhibitors in general. Although the data base for agents GA, GB, and GD were lacking reproductive and developmental toxicity data to some extent, a UFD of 3 was justified for the aforementioned reasons. The data base for agent VX was considered complete and a UFD of 1 was selected for development of the RfD for this agent. A modifying factor (MF) to reflect qualitative assessment of additional uncertainties in the critical study or data base that are not addressed by uncertainty factors was limited to agent GA due to the route-to-route (i.e., intraperitoneal to oral) extrapolation and to insure the equivalent oral NOAEL was not overestimated. This article provides a brief overview of the nerve agents, information on cholinergic systems that is pertinent to deriving toxicity values for nerve agents and other organophosphate cholinesterase inhibitors, and a discussion of key issues regarding the use of uncertainty factors in RfD derivations.

Mouse liver tumor data: assessment of carcinogenic activity.

Significant numbers of chemicals have been shown to be carcinogenic in mouse liver although they do not exhibit carcinogenic activity in other organs or tissues of mice or rats. This review focuses on the reasons for the unique susceptibility of the mouse liver to these carcinogens and the extent to which the carcinogenic activity of a chemical in mouse liver can be used to predict carcinogenicity in humans. Many of these mouse liver carcinogens lack genotoxic activity and, as such, have been proposed to be tumor promoters. Two mechanisms that may explain the action of nongenotoxic carcinogens in mouse liver are reviewed. These are: direct action on precursor cancer cells, either to accelerate their growth or to prevent their death and the selective growth advantage, resulting from regenerative hyperplasia of precursor cancer cells in response to the necrosis of normal cells produced by hepatotoxins. Estimating human health risks on the basis of mouse liver tumor data is believed to differ for nongenotoxic and genotoxic carcinogens in two fundamental ways. The first involves intraspecies extrapolation and the second involves low-dose extrapolation. In conclusion, although mouse liver tumor data are seen to be of value in estimating human health hazard, it is important to distinguish between genotoxic and nongenotoxic mechanisms in applying such data. Further study of the biochemical and molecular mechanisms of chemical carcinogens is necessary to determine the relationship between their activity in mouse liver and their activity in humans.

Human health hazards associated with chemical contamination of aquatic environment.

Given the finite supply of water available for human use, continued chemical contamination of the aquatic environment may pose a significant human health hazard. Consequently, an effort must be made to develop ambient water quality criteria to protect human health and preserve the integrity of the aquatic environment. In developing water quality criteria based on human health effects, information on sources of exposure, pharmacokinetics, and adverse effects must be carefully evaluated. Information on sources of exposure is needed to determine the contribution of exposure from water relative to all other sources. Pharmacokinetic data are used in inter- and intraspecies extrapolation and in characterizing the mode of toxic action. Information on toxic effects includes data on acute, subchronic, and chronic toxicity, mutagenicity, teratogenicity, and carcinogenicity. In analyzing such information, a distinction is made between threshold and nonthreshold effects. Currently, carcinogenicity and mutagenicity are considered to be nonthreshold effects. For carcinogens and mutagens, criteria are calculated by postulating an "acceptable" increased level of risk and using extrapolation models to estimate the dose which would result in this increased level of risk. For other chemicals, thresholds are assumed and criteria are calculated by deriving "acceptable daily intakes" for man which would presumably result in no observable adverse effects. Neither process is exact, and attempts must be made to improve and verify risk assessment methodologies.