Оценка риска комбинированного воздействия химических веществ

В этом документе описана методическая схема оценки риска комбинированного воздействия нескольких химических веществ, разработанная на основе материалов семинара по оценке агрегированного/кумулятивного риска (Комбинированное воздействие нескольких химических веществ), организованного Всемирной Организацией Здравоохранения (ВОЗ) и Международной Программой по Химической Безопасности (МПХБ), который состоялся в 2007 году. Методическая схема предназначена для помощи специалистам по оценке риска в определении приоритетов при управлении рисками для широкого спектра применений, когда ожидается совместная экспозиция различными химическими веществам. Она основана на иерархическом (поэтапном) подходе, который предполагает комплексное и итеративное (повторяющееся) рассмотрение воздействия и опасности на всех этапах, при этом каждый уровень становится все более углубленным (т.е. менее консервативным и более определенным) чем предыдущий, но более трудоемким и интенсивным при обработке данных. Она включает в себя ссылки на прогнозирующую и вероятностную методологию на различных уровнях в дополнение к гибкому учету неопределенностей. К документу также приложены описания двух исследований, которые были проведены для проверки и уточнения методической схемы.

Identifying important life stages for monitoring and assessing risks from exposures to environmental contaminants: results of a World Health Organization review.

In this paper, we summarize exposure-related issues to consider in determining the most appropriate age ranges and life stages for risk assessment. We then propose a harmonized set of age bins for monitoring and assessing risks from exposures to chemicals for global use. The focus is on preconception through adolescence, though the approach should be applicable to additional life stages. A two-tiered set of early life age groups is recommended. The first tier involves the adoption of guidance similar to the childhood age groups recommended by the U.S. Environmental Protection Agency, whereas the second tier consolidates some of those age groups to reduce the burden of developing age-specific exposure factors for different regions. While there is no single "correct" means of choosing a common set of age groups to use internationally in assessing early life exposure and risk, use of a set of defined age groups is recommended to facilitate comparisons of potential exposures and risks around the globe, the collection of data and analyses of aggregate exposure and cumulative risk. Application of these age groups for robust assessment of exposure and risk for specific populations will require region-specific exposure factors as well as local environmental monitoring data.

Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework.

This paper describes a framework for the risk assessment of combined exposure to multiple chemicals based on and developed subsequent to the World Health Organization/International Programme on Chemical Safety Workshop on Aggregate/Cumulative Risk Assessment (Combined Exposures to Multiple Chemicals) held in 2007. The framework is designed to aid risk assessors in identifying priorities for risk management for a wide range of applications where co-exposures to multiple chemicals are expected. It is based on a hierarchical (phased) approach that involves integrated and iterative consideration of exposure and hazard at all phases, with each tier being more refined (i.e., less cautious and more certain) than the previous one, but more labor and data intensive. It includes reference to predictive and probabilistic methodology in various tiers in addition to tiered consideration of uncertainty. The paper also annexes two case studies that have been developed to test and refine the framework.

Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the International Life Sciences Institute (ILSI) Research Foundation (RF), and the ILSI Health and Environmental Sciences Institute (HESI) hosted a workshop in November 2009 to review current practice in the application of mode of action (MOA) considerations in chemical risk assessment. The aim was to provide a rationale for a more general, but flexible approach and to propose steps to facilitate broader uptake and use of the MOA concept. There was consensus amongst the workshop participants that it will require substantial effort and cooperation from the multiple disciplines involved to embrace a common, consistent, and transparent approach. Setting up a repository of accepted MOAs and associated guidance concerning appropriate data to support specific MOAs for critical effects would facilitate categorization of chemicals and allow predictions of toxicity outcomes by read-across. This should in future contribute to the reduction of toxicity testing in animals. The workshop participants also acknowledged the value and importance of human data and the importance of integrating information from biological pathway analyses into current MOA/human relevance frameworks.

Knowns and unknowns on burden of disease due to chemicals: a systematic review.

BACKGROUND: Continuous exposure to many chemicals, including through air, water, food, or other media and products results in health impacts which have been well assessed, however little is known about the total disease burden related to chemicals. This is important to know for overall policy actions and priorities. In this article the known burden related to selected chemicals or their mixtures, main data gaps, and the link to public health policy are reviewed. METHODS: A systematic review of the literature for global burden of disease estimates from chemicals was conducted. Global disease due to chemicals was estimated using standard methodology of the Global Burden of Disease. RESULTS: In total, 4.9 million deaths (8.3% of total) and 86 million Disability-Adjusted Life Years (DALYs) (5.7% of total) were attributable to environmental exposure and management of selected chemicals in 2004. The largest contributors include indoor smoke from solid fuel use, outdoor air pollution and second-hand smoke, with 2.0, 1.2 and 0.6 million deaths annually. These are followed by occupational particulates, chemicals involved in acute poisonings, and pesticides involved in self-poisonings, with 375,000, 240,000 and 186,000 annual deaths, respectively. CONCLUSIONS: The known burden due to chemicals is considerable. This information supports decision-making in programmes having a role to play in reducing human exposure to toxic chemicals. These figures present only a number of chemicals for which data are available, therefore, they are more likely an underestimate of the actual burden. Chemicals with known health effects, such as dioxins, cadmium, mercury or chronic exposure to pesticides could not be included in this article due to incomplete data and information. Effective public health interventions are known to manage chemicals and limit their public health impacts and should be implemented at national and international levels.

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.

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.

Skin sensitization in chemical risk assessment: report of a WHO/IPCS international workshop focusing on dose-response assessment.

An international workshop was held in 2006 to evaluate experimental techniques for hazard identification and hazard characterization of sensitizing agents in terms of their ability to produce data, including dose-response information, to inform risk assessment. Human testing to identify skin sensitizers is discouraged for ethical reasons. Animal-free alternatives, such as quantitative structure-activity relationships and in vitro testing approaches, have not been sufficiently developed for such application. Guinea pig tests do not generally include dose-response assessment and are therefore not designed for the assessment of potency, defined as the relative ability of a chemical to induce sensitization in a previously naive individual. In contrast, the mouse local lymph node assay does include dose-response assessment and is appropriate for this purpose. Epidemiological evidence can be used only under certain circumstances for the evaluation of the sensitizing potency of chemicals, as it reflects degree of exposure as well as intrinsic potency. Nevertheless, human diagnostic patch test data and quantitative elicitation data have provided very important information in reducing allergic contact dermatitis risk and sensitization in the general population. It is therefore recommended that clinical data, particularly dose-response data derived from sensitized patients, be included in risk assessment.

IPCS framework for analyzing the relevance of a cancer mode of action for humans.

The use of structured frameworks can be invaluable in promoting harmonization in the assessment of chemical risk. IPCS has therefore updated and extended its mode of action (MOA) framework for cancer to address the issue of human relevance of a carcinogenic response observed in an experimental study. The first stage is to determine whether it is possible to establish an MOA. This comprises a series of key events along the causal pathway to cancer, identified using a weight-of-evidence approach based on the Bradford Hill criteria. The key events are then compared first qualitatively and then quantitatively between the experimental animals and humans. Finally, a clear statement of confidence, analysis, and implications is produced. The IPCS human relevance framework for cancer provides an analytical tool to enable the transparent evaluation of the data, identification of key data gaps, and structured presentation of information that would be of value in the further risk assessment of the compound, even if relevancy cannot be excluded. This might include data on the shape of the dose-response curve, identification of any thresholds and recognition of potentially susceptible subgroups, for example, the basis of genetic or life-stage differences.

Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18-20 April 2002.

This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in developmental toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions. There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and developmental toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application.