International Programme On Chemical Safety Research Articles

Contaminantes ambientais e os interferentes endócrinos

The toxicity of various pollutants has been routinely investigated according to their teratogenic and carcinogenic effects. In the last few decades, however, many of such pollutants have been shown to adversely affect the endocrine system of human beings and other species. Currently, more than eleven million chemical substances are known in the world, and approximately 3,000 are produced on a large scale. Numerous chemical composites of domestic, industrial and agricultural use have been shown to influence hormonal activity. Examples of such chemical products with estrogenic activity are substances used in cosmetics, anabolizing substances for animal feeding, phytoestrogens and persistent organic pollutants (POPs). These agents are seen in residential, industrial and urban sewerage system effluents and represent an important source of environmental contamination. The International Programme on Chemical Safety (IPCS) defines as endocrine disruptors substances or mixtures seen in the environment capable of interfering with endocrine system functions resulting in adverse effects in an intact organism or its offspring. In this article the authors present a current literature review about the role of these pollutants in endocrine and metabolic diseases, probable mechanisms of action, and suggest paths of investigation and possible strategies for prevention and reduction of its possible damages.

Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme

Since the publication of the International Programme on Chemical Safety (IPCS) Harmonized Scheme for Mutagenicity Testing, there have been a number of publications addressing test strategies for mutagenicity. Safety assessments of substances with regard to genotoxicity are generally based on a combination of tests to assess effects on three major end points of genetic damage associated with human disease: gene mutation, clastogenicity and aneuploidy. It is now clear from the results of international collaborative studies and the large databases that are currently available for the assays evaluated that no single assay can detect all genotoxic substances. The World Health Organization therefore decided to update the IPCS Harmonized Scheme for Mutagenicity Testing as part of the IPCS project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. The approach presented in this paper focuses on the identification of mutagens and genotoxic carcinogens. Selection of appropriate in vitro and in vivo tests as well as a strategy for germ cell testing are described.

Chromium nitrate as a source of chromium added for nutritional purposes to food supplements

Chromium nitrate as a source of chromium added for nutritional purposes to food supplements

Preventive Effects of Taurine and Vitamin C on Renal DNA Damage of Mice Exposed to Arsenic

Arsenic (As), as a pollutant, ubiquitously exists in well water and contaminated soil. There is also exposure to arsenic in some industries, such as non-ferrous smelting, wood preservation, and electronics. The risk of Asinduced human diseases is high in some developing countries such as Bangladesh, India, and China . Epidemiologic investigations and animal experiments have demonstrated that acute and chronic exposure to As can cause injury to the kidney and increase the risk of renal cancer, so the kidney may be a major target of toxicities induced by As. It was reported that As depresses the functions of the antioxidant defense system and led to oxidative damage to cellular macromolecules . The above results show that increase of oxidative stress and subsequent oxidative DNA damage of cells may be involved in the renal disorders induced by As. Taurine, an end product of l-cysteine metabolism, is the most abundant free amino acid in many tissues and protects against the adverse effects of reactive oxygen species (ROS) caused by various toxic substances. Vitamin C (Vit C), as a kind of water-soluble antioxidant, also prevents oxidative damage to many important macromolecules. 8-OHdG is formed from deoxyguanosine (dG) in DNA by hydroxy free radicals. Because of its stability, 8-OHdG is known as one of the most reliable markers of oxidative DNA damage. In the present study, in order to investigate the protective effects of taurine and Vit C against As-induced nephrotoxicity, we examined the expression of 8-OHdG and the histopathological changes in the renal tissues of mice administered As or both As and taurine or Vit C.

IPCS Framework for Analyzing the Relevance of a Noncancer Mode of Action for Humans

Structured frameworks are extremely useful in promoting transparent, harmonized approaches to the risk assessment of chemicals. One area where this has been particularly successful is in the analysis of modes of action (MOAs) for chemical carcinogens in experimental animals and their relevance to humans. The International Programme on Chemical Safety (IPCS) recently published an updated version of its MOA framework in animals to address human relevance (cancer human relevance framework, or HRF). This work has now been extended to noncancer effects, with the eventual objective of harmonizing framework approaches to both cancer and noncancer endpoints. As in the cancer HRF, the first step is to determine whether the weight of evidence based on experimental observations is sufficient to establish a hypothesized MOA. This comprises a series of key events causally related to the toxic effect, identified using an approach based on the Bradford Hill criteria. These events are then compared qualitatively and, next, quantitatively between experimental animals and humans. The output of the analysis is a clear statement of conclusions, together with the confidence, analysis, and implications of the findings. This framework provides a means of ensuring a transparent evaluation of the data, identification of key data gaps and of information that would be of value in the further risk assessment of the compound, such as on dose–response relationships, and recognition of potentially susceptible subgroups, for example, based on life-stage considerations.

From Smoke Inhalation to Chemical Attacks: Acute Cyanide Poisoning in the Prehospital Setting

The International Programme on Chemical Safety (IPCS)—a cooperative program of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP)—designates cyanide a priority chemical in relation to the potential impact on human health and the environment. Like other IPCS priority chemicals, cyanide is highly toxic, is a transboundary safety concern, is a target for risk management in multiple countries, is produced in large quantities, has dispersive use, and poses a risk for human exposure (Table 1). Acute exposure to cyanide has caused significant morbidity and mortality in household and industrial accidents, as well as in suicides and attempted genocides, wars, and acts of terrorism. The most common, but perhaps least recognized source of cyanide in cases of acute poisoning is from smoke caused by fires. This review is the product of a collaboration among experts in prehospital emergency medicine, public health and safety, and disaster preparedness. Current understanding of the causes, consequences, and management of cyanide poisoning are described as a potential advancement in antidotal therapy that could transform the provision of prehospital care to cyanide-poisoned victims.

Evidence for genotoxicity of pesticides in pesticide applicators: a review

A systematic review of the literature has been conducted and studies reporting investigations of genotoxicity biomarkers in pesticide workers have been assessed with view to establishing whether there was evidence for any risk to those using pesticides approved in the United Kingdom. Each of the studies was evaluated using a set of criteria drawn up by members of the UK Committee of Mutagenicity based upon the guidelines proposed by the International Programme on Chemical Safety (IPCS) working group [R. J. Albertini, D. Anderson, G. R. Douglas, L. Hagmar, K. Hemminki, F. Merlo, A. T. Natarajan, H. Norppa, D. E. Shuker, R. Tice, M. D. Waters and A. Aitio (2000) Mutat. Res., 463, 111-172]; 24 out of 70 studies met the criteria for inclusion in the substantive evaluation. Positive findings were compared with occupational practices and evidence of exposure to specific pesticides with view to developing hypotheses for further consideration. Seventeen of the 24 studies reported positive findings, although in the majority of these the magnitude of increase was small. There was some limited evidence that the use of benzimidazoles was more consistently associated with positive findings. However, limitations in the data, particularly evidence of exposure, did not allow definitive conclusions to be drawn. Also, it was noted that the use (or not) of personal protective equipment (PPE) was not well documented and in the few studies in which its use was reported, the findings were more likely to be positive in the absence of PPE usage. An independent epidemiological review concluded that all studies were of limited design, particularly with regards to study size, the assessment of subject selection and potential recruitment bias. Variance in genotoxicity indices in the control population and a lack of understanding of the factors influencing this variability complicate attempts to characterize positive responses. More substantive data are needed in this respect so that the significance of relatively small increases in biomonitoring indices can be accurately assessed. Once these data are available, a study in workers using benzimidazoles would be appropriate.

Data considerations for regulation of water contaminants

There are several pieces of legislation based on human health assessment that set the framework for U.S. EPA's regulation of water contaminants, such as bromate. The Safe Drinking Water Act, for example, specifies that the best available science be used in support of regulation of drinking water contaminants, and highlights that regulations must provide protection to sensitive human populations. Recent EPA guidance, including the 2005 Cancer Guidelines, emphasize analyzing data, and using defaults only in the absence of adequate data. This represents a major shift from the former practice of invoking default methodologies or values unless it was judged that there were sufficient data to depart from them. The Guidelines further present a framework for assessing data in order to determine if a mode of action (MOA) can be established, based on a modification of the Bradford–Hill criteria for causality. A similar approach is used by the International Programme on Chemical Safety (IPCS). To illustrate the application of the framework for evaluating animal tumors, three case studies are considered here. In the first example (chloroform carcinogenicity), sufficient data exist to identify the MOA in animals, and the data are used to illustrate the evaluation of the plausibility of the animal MOA in humans, taking into account toxicokinetics and toxicodynamics. In this case, the MOA was judged to be relevant to humans, and was used to determine the approach for the cancer quantitation. In the second example (naphthalene inhalation carcinogenicity), the key question is whether the weight of evidence (WOE) is sufficient to establish the MOA in animals. Atrazine-induced mammary tumors form the final example, illustrating the reasoning used to determine that the tumor MOA in animals was not considered relevant to humans; atrazine is therefore considered not likely to be a human carcinogen.

Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.

ESTIMATED EXPOSURE TO PHTHALATES IN COSMETICS AND RISK ASSESSMENT

Some phthalates such as di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) and their metabolites are suspected of producing teratogenic or endocrine-disrupting effects. To predict possible human exposure to phthalates in cosmetics, the levels of DEHP, diethyl phthalate (DEP), DBP, and butylbenzyl phthalate (BBP) were determined by high-performance liquid chromatography (HPLC) in 102 branded hair sprays, perfumes, deodorants, and nail polishes. DBP was detected in 19 of the 21 nail polishes and in 11 of the 42 perfumes, and DEP was detected in 24 of the 42 perfumes and 2 of the 8 deodorants. Median exposure levels to phthalates in cosmetics by dermal absorption were estimated to be 0.0006 µg/kg body weight (bw)/d for DEHP, 0.6 µg/kg bw/d for DEP, and 0.103 µg/kg bw/d for DBP. Furthermore, if phthalates in cosmetics were assumed to be absorbed exclusively via 100% inhalation, the median daily exposure levels to phthalates in cosmetics were estimated to be 0.026 µg/kg bw/d for DEHP, 81.471 µg/kg bw/d for DEP, and 22.917 µg/kg bw/d for DBP, which are far lower than the regulation levels set buy the Scientific Committee on Toxicity, Ecotoxicity, and the Environment (CSTEE) (37 µg/kg bw/d, DEHP), Agency for Toxic Substances and Disease Registry (ATSDR) (7000 µg/kg bw/d, DEP), and International Programme on Chemical Safety (IPCS) (66 µg/kg bw/d, DBP), respectively. Based on these data, hazard indices (HI, daily exposure level/regulation level) were calculated to be 0.0007 for DEHP, 0.012 for DEP, and 0.347 for DBP. These data suggest that estimated exposure to phthalates in the cosmetics mentioned are relatively small. However, total exposure levels from several sources may be greater and require further investigation.

Adoption of an official ISEA glossary

The International Society for Exposure Analysis (ISEA) and its Nomenclature Committee have been involved since the mid-1990s in an intermittent but ongoing effort to develop an official ISEA glossary. Several related activities have stimulated greater interest and discussion nationally and internationally on a common exposure language. Among these activities are a 1997 Journal of Exposure Analysis and Environmental Epidemiology feature article on exposure and dose definitions and a 1999-initiated project of the International Programme on Chemical Safety (IPCS) (WHO/ILO/UNEP) to confront terminology issues hindering harmonization in the area of exposure assessment. Recently, the ISEA members voted in support of adopting the IPCS glossary as the official ISEA glossary, and the ISEA Executive Board agreed to accept this recommendation. In this feature article, we (1) describe the process through which the ISEA adopted the IPCS glossary as the official ISEA glossary, (2) present the joint IPCS/ISEA glossary of terms and their definitions, and (3) discuss plans for how the glossary can be used by ISEA and updated over time by ISEA and IPCS. The glossary is intended to be a living document that reflects the latest usage and maintains international harmonization of exposure terminology that can be practically applied to improve communication in exposure and related fields.

Policies in place throughout the world: action by the European Union

Policies in place throughout the world: action by the European Union

The Role of Metabolism in Establishing Chemical-Specific Adjustment Factors for n-Hexane and Methyl n-Butyl Ketone

ABSTRACT This paper focuses on the derivation of chemical-specific adjustment factors (CSAFs) for two neurotoxic solvents, n-hexane and methyl n-butyl ketone (MBK). Workers are exposed to the chemicals mainly via inhalation when they are used, for example, as solvents in adhesives. In order to derive CSAFs for n-hexane and MBK, research data were used from animal studies conducted in our laboratory. Also, MEDLINE and TOXLINE databases were searched for references containing animal and human toxicokinetic and toxicodynamic data. International Programme on Chemical Safety (IPCS) guidelines were followed. From the available data, the composite factor (CF) for n-hexane was calculated to be 18.2. Because n-hexane and MBK are most often used in combination with other solvents, e.g., methyl ethyl ketone (MEK), the metabolic induction of the toxicity of n-hexane or MBK by MEK should be considered in the derivation of CSAFs. However, in the presence of MEK the calculated CF for both n-hexane and MBK is 13. As more human data become available, the CFs for the mixtures may be reduced compared to the individual chemicals.

ILO activities in the area of chemical safety

The ILO has been active in the area of safety in the use of chemicals at work since the year of its creation in 1919, including the development of international treaties and other technical instruments, the provision of technical assistance to its member States, and the development of chemical safety information systems. The two key ILO standards in this area are the Conventions on safety in the use of chemicals at work (No. 170, 1990), and the Prevention of Major Industrial Accidents (No. 174, 1993). The ILO Programme on occupational safety, health and environment (Safe Work) is currently responsible for ILO chemical safety activities. In the past two decades, most of ILO work in this area has been carried out within the context of inter-agency collaboration frameworks linking the ILO, WHO, UNEP, FAO, UNIDO, UNITAR, and the OECD, including the International Programme on Chemical Safety (IPCS), the Inter-Organisation Programme for the Sound Management of Chemicals (IOMC), and the Intergovernmental Forum on Chemical Safety (IFCS). Apart from the regular development, updating and dissemination of chemical safety information data bases such as the IPCS International Chemical Cards, the elaboration of a Globally harmonized system for the classification and labelling of Chemicals (GHS) has been the most outstanding achievement of this international collaboration on chemical safety.

Global information network on chemicals (GINC) and its Asian component.

The Global Information Network on Chemicals (GINC) is an effort to build a global information network that links international, national, and other organizations working for the safe management of chemicals in order to exchange information and improve communications. The project was originally proposed in 1993 by one of the authors then at the National Institute of Health Sciences (NIHS) of Japan to the International Program on Chemical Safety (IPCS), which is a joint project of World Health Organization (WHO), International Labor Organization (ILO), and United Nations Environment Program (UNEP). The base support system was first implemented at NIHS using the Internet/World Wide Web (WWW) technology in 1995. The project was then endorsed by the Intergovernmental Forum on Chemical Safety (IFCS) and was adopted by the Inter-Organization Program for the Sound Management of Chemicals (IOMC). However, the base system (http://www.nihs.go.jp/GINC/index.html) has been developed and maintained solely by the NIHS group under the support of the Ministry of Health and Welfare (MHW), Japan. Asia, particularly East Asia and the Pacific region, was chosen as the feasibility study region for this project. During the period from December 1994 to July 2002, NIHS hosted eight meetings on this project held in Tokyo.

Framework for the Integration of Health and Ecological Risk Assessment

The World Health Organization's International Programme on Chemical Safety (IPCS), the Organization for Economic Cooperation and Development (OECD), and the U.S. Environmental Protection Agency have developed a collaborative partnership to foster integration of assessment approaches for human health and ecological risks. This paper presents the framework developed by that group. Integration provides coherent expressions of assessment results, incorporates the interdependence of humans and the environment, uses sentinel organisms, and improves the efficiency and quality of assessments relative to independent human health and ecological risk assessments. The paper describes how integration can occur within each component of risk assessment, and communicates the benefits of integration at each point. The goal of this effort is to promote the use of this internationally accepted guidance as a basis for harmonization of risk assessment.

Practical application of kinetic data in risk assessment—an IPCS initiative

In this paper, guidance developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals is considered in the context of its application in the assessment of the adequacy of physiological–toxicokinetic (PTK) modeling to inform quantitatively extrapolations for interspecies differences and human variability in dose–response assessment. This guidance was developed in the context of a framework, which permits the incorporation of quantitative chemical-specific data, relating to either toxicokinetics or toxicodynamics to replace part or all of the usual 100-fold default uncertainty factor for interspecies differences or human variability in the development of tolerable or reference doses or concentrations. However, since the guidance relates specifically to adequacy of kinetic or dynamic data to replace default for interspecies and human variability, it is also applicable to other approaches of dose–response analyses such as estimation of cancer potency or risk. The framework also supports probabilistic characterization, where data are sufficient. This guidance has been developed and refined through a series of planning and technical meetings and larger workshops, in which a broad range of participants from academia, government agencies, and the private sector have prepared and gained experience in application through case studies. The guidance for adequacy of kinetic data to replace default is presented in the context of several categories, including determination of the active chemical species, choice of the appropriate kinetic parameter and experimental data, the latter which includes reference to relevance of population, relevance of route, relevance of dose/concentration, and adequacy of number of subjects/samples. The principal objective of this guidance, which has been developed primarily as a resource for risk assessors, is to foster better understanding of the criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics, including PTK models. It is anticipated that the guidance will also encourage generation of appropriate data and models, and facilitate their incorporation in dose/concentration–response assessment for regulatory purposes. In this paper, the application of the guidance is considered primarily through reference to examples, with emphasis on those where PTK models have been informative.

Incorporating mechanistic data into risk assessment

Incorporating mechanistic data into risk assessment is intended to improve the overall scientific validity, and thereby reduce the uncertainty, in human risk analysis. Relevant mechanistic data provides a link between the molecular and cellular event(s) and adverse outcome, and insight into mechanism of action is critical for accurate evaluation of dose–response relationships and inter-species extrapolation. This paper provides an example of applying mechanistic data to human risk assessment using the frameworks outlined by the International Programme on Chemical Safety (IPCS) and the U.S. Environmental Protection Agency (USEPA). Key components of the data are used to address the strength and consistency of the mechanism and to apply these data to human risk characterization.

Guidance for Derivation of Chemical-Specific Adjustment Factors (CSAF)—Development and Implementation

This manuscript addresses the content of and considerations in the implementation of guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for inter-species differences and human variability in dose response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector.The guidance for adequacy of data for replacement of defaults for interspecies differences and human variability commonly adopted in the derivation of Tolerable or Acceptable Intakes is presented principally through illustrative reference to case examples. The relevant guidance is addressed in the context of several generic categories, including determination of the active chemical species, choice of the appropriate kinetic parameter or endpoint (dynamic component) and nature of experimental data, the latter, which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples

Guidelines for application of chemical-specific adjustment factors in dose/concentration–response assessment

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose–response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose–response assessment for regulatory purposes (IPCS, 2001).