An approach to investigating the importance of high potency polycyclic aromatic hydrocarbons (PAHs) in the induction of lung cancer by air pollution.

Evidence suggests that people living in urban areas have an increased risk of lung cancer due to higher levels of air pollution in these areas. Benzo[a]pyrene (B[a]P) is currently used as the main indicator of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in air pollution, but there is concern that B[a]P may not be the ideal surrogate of choice for PAH mixtures since higher potency PAHs have recently been identified which could potentially contribute more and variably to the overall carcinogenicity. Dibenzo[a,h]anthracene (DBA) and dibenzo[a,l]pyrene (DB[a,l]P) are estimated to have carcinogenic potencies 10 or more times greater than B[a]P but data on their presence and formation in the environment are limited. Several occupational and environmental PAH biomonitoring studies are reviewed here, with particular focus on the specific exposure groups, study design, sample tissue, in particular the use of nasal tissues, and biomarkers used in each study. Consideration of these data is then used to propose a novel biomonitoring approach to evaluate exposure, uptake and the role of high potency PAHs in air pollution-related lung cancer. This is based upon an occupational study examining specific DNA adducts for DBA and DB[a,l]P in nasal cells to evaluate the extent to which these high potency PAHs might contribute to the increased risk of developing lung cancer from air pollution.

Approaches to carcinogenic risk assessment for polycyclic aromatic hydrocarbons: a UK perspective.

This paper reviews the approaches to carcinogenic risk assessment of polycyclic aromatic hydrocarbons (PAHs) in air pollution with emphasis on high potency PAHs such as dibenzo[a,l]pyrene (DB[a,l]P). The potency of DB[a,l]P may be 100-fold greater than benzo[a]pyrene (B[a]P); thus the B[a]P surrogate approach currently used to monitor for compliance with UK air pollution standards may not be appropriate. It is suggested that an approach based on potency equivalency factors (PEFs) could be developed to include highly potent PAHs provided an appropriate reference data set for relevant PAHs using a route acceptable for inhalation risk assessment is selected. Available data suggest that intratracheal administration of low doses of PAHs to rats is likely to simulate the kinetics of inhalation exposure to PAHs in a feasible manner. The use of a measure of total DNA adducts as an endpoint, which correlates well with lung tumourigenicity, would provide surrogate data for setting PEFs without the need for long-term bioassays in rodents. Further, dose-response studies using intratracheal administration of a range of PAHs singly and in combination to assess additivity are required to develop a PEF system for inhalation PEFs derived from DNA adduct measurements.

Local lymph node assay - validation, conduct and use in practice.

The validation of alternative methods is a relatively new activity in toxicology. The local lymph node assay (LLNA), a novel method for the identification of chemicals that have the potential to cause skin sensitization, was the first test to pass through the formal regulatory validation process established in the USA under the auspices of ICCVAM, the Interagency Coordinating Committee on the Validation of Alternative Methods. ICCVAM approved the LLNA as an alternative to guinea pig tests for the identification of skin sensitisation hazards. In this report, we explore the nine recommendations made by ICCVAM and discuss their interpretation in relation to the new OECD Guideline 429, which describes the LLNA. In particular, the value and limitations of the use of statistical evaluation of data and of the inclusion of routine positive controls is examined. It is concluded that the OECD Guideline as currently written embodies the necessary flexibility to permit conduct of the LLNA in a manner necessary to meet the varying needs of regulatory agencies and toxicologists around the world.

IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis.

The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project.

Mouse-specific carcinogens: an assessment of hazard and significance for validation of short-term carcinogenicity bioassays in transgenic mice.

1. The International Conference on the Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for human use (ICH) has agreed that bioassay data from only one species, the rat, supported by appropriate mutagenicity and pharmacokinetic data and also information from new (unvalidated) short term in vivo screening tests for potential carcinogenicity, could be used for the licensing of human medicines. This proposal has been supported by reviews of the utility of testing pharmaceuticals in the mouse which have concluded that the mouse bioassay contributes little to regulatory decisions. The current review was undertaken to identify 'genuine' mouse-specific carcinogens using the Gold Carcinogenicity Potency Database (CPD) for the initial identification of potential mouse-specific carcinogens from published literature. Hazard assessments were completed for these chemicals with particular attention focused on the 'genuine' mouse-specific carcinogens. The significance of such chemicals has been discussed together with consideration of on-going work on the validation of short-term carcinogenicity bioassays using transgenic mice. 2. Seventy-six potential mouse specific carcinogens were identified through the Gold Carcinogenicity Potency Database. Following more detailed consideration a total of ten chemicals were excluded from further consideration (three were multispecies carcinogens, five were considered to be non-carcinogenic in the mouse, and the data for two were uninterpretable). The review focused on the remaining 66 chemicals. There was equivocal evidence of carcinogenicity to the rat for 28 chemicals and inadequate data for a further 23 chemicals. Fifteen 'genuine' mouse-specific carcinogens were identified. These 15 chemicals comprise two genotoxic mouse-specific carcinogens (N-methylolacrylamide (924-42-5), 2,6-Dichloro-p-phenylenediamine (609-20-1); five non-genotoxic mouse-specific carcinogens 2-Aminobiphenyl.HCl (2185-92-4), Captan (133-06-2), Dieldrin (60-57-7), Diethylhexyladipate (103-23-1), and Probenicid (57-66-9); five mouse-specific carcinogens with equivocal evidence of mutagenicity were identified; (2,4-diaminophenol.2HCl (137-09-7), Dipyrone (68-89-3), Ozone (10028-15-6), Vinylidene chloride (75-35-4), and Zearalenone (17924-92-4)), and three mouse-specific carcinogens with inadequate mutagenicity data (Benzaldehyde (100-52-7), Piperonyl sulphoxide (120-62-7), Ripazepam (26308-28-1)). 3. It is suggested that the two genotoxic mouse carcinogens would have been considered as potential carcinogens in the absence of a mouse bioassay. Of the five non-genotoxic mouse-specific carcinogens; three induced tumours in mouse liver only and are considered as being of low potential hazard to human health. The remaining two chemicals would have been missed in the absence of a mouse bioassay (2-aminobiphenyl (2185-92-4) and captan (133-06-2)) and thus are good candidates for evaluation in the short term bioassays in transgenic mice currently being validated. 4. The hardest group of mouse-specific carcinogens to evaluate are those for which there is equivocal or inadequate mutagenicity data. The difficulty in evaluating these particular chemicals emphasises the need for adequate mutagenicity data in addition to adequate carcinogenicity data in order to assess potential hazards to human health. Hazard assessments and a consideration of the potential role for short-term bioassays in transgenic mice for the eight chemicals in this subgroup are presented. 5. A number of general conclusions have been derived from this review. Firstly, there are insufficient published genotoxicity data to allow a full assessment fo mutagenic potential for 57/76 of the potential mouse-specific carcinogens identified from the CPD. This is surprising given the clear value of such data in interpreting bioassay results and the much greater resources required for carcinogenicity bioassays. (ABSTRACT TRUNCATED)

Setting air quality standards for carcinogens: an alternative to mathematical quantitative risk assessment-discussion paper.

It has been accepted in many countries that the regulation of ambient air quality should involve the use of health-based air quality standards. Setting standards for air pollutants which are genotoxic carcinogens presents difficult problems to the regulator, in that the prediction of the effects on health of low levels of exposure is suspected to be inaccurate, and is not currently amenable to either experimental or epidemiological verification. In some countries, techniques of mathematical quantitative risk assessment have been adopted to calculate acceptable levels of exposure to, or the unit risk factors for, genotoxic carcinogens. We regard these approaches as unsatisfactory. An alternative approach, based upon a number of argued premises, a strategy which identifies decision points and the cautious application of uncertainty factors, is described.

Risk assessment of butadiene in ambient air; the approach used in the UK.

The UK Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC) and the related Committee on Mutagenicity provided advice on 1,3-butadiene in 1992. This followed detailed consideration of the available mutagenicity, animal carcinogenicity and epidemiology data plus information on toxicokinetics. They concluded that 1,3-butadiene was an in vivo mutagen, a potent genotoxic animal carcinogen and should be regarded as a probable human carcinogen. The Department of Health is not aware of more recent data warranting reconsideration of these conclusions. General advice on setting air quality standards for carcinogenic air pollutants was given by the COC. Although the prudent assumption of the absence of any safe level for genotoxic carcinogens was preferred, a pragmatic approach based essentially on assessment of the exposure at which no increased risk would be detected, plus a safety factor, was considered reasonable for compounds like butadiene where exposure cannot be totally avoided. This approach, plus recognition that it is unadvisable to allow ambient levels of genotoxic carcinogens to rise, is used in the UK. The procedure by which the Department of Environment's Expert Panel on Air Quality Standards recommended a value of 1 ppb for butadiene based on these principles is described.

Carcinogens in food: priorities for regulatory action.

A pragmatic possible approach to the prioritization of chemical carcinogens occurring as food contaminants is described, based on the carcinogenic risk to the population. This should be of value in ensuring that resources for assessment and management of carcinogens in food are directed to the most important areas with regard to carcinogenic risk to the population. Key components of this approach are an assessment of the carcinogenic hazard to humans combined with estimations of intakes per person and of the proportion of the population exposed. These are used to derive an index referred to as the Population Carcinogenic Index. Concerning the hazard assessment expert judgement is used to place the chemical in one of five categories. The highest category is for chemical carcinogens that are believed to act by a genotoxic mechanism. It is recognised that such compounds may vary enormously with respect to their potency and various approaches to ranking carcinogens on the basis of potency are reviewed. The approach adopted is to subdivide the genotoxic carcinogens category into high, medium and low potency based on the TD50 value. Methods of estimating intakes and exposed populations are considered and an approach which groups these into broad categories is developed. The hazard and exposure assessments are then combined to derive the Population Carcinogenicity Index.

IPCS harmonization of methods for the prediction and quantification of human carcinogenic/mutagenic hazard, and for indicating the probable mechanism of action of carcinogens.

A flow chart is presented as a recommended sequence of tests to predict the carcinogenic hazard, and to predict and quantify the mutagenic hazard to germ cells of chemicals to humans. Ten associated principles of testing for these endpoints are also suggested. These recommendations are the result of a meeting convened under the auspices of the International Programme on Chemical Safety (IPCS), as part of their project on 'Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals'. The meeting was held at Carshalton, Surrey, from 13-17 February 1995.

Intermodal agreement of follow-up telephone functional assessment using the Functional Independence Measure in patients with stroke.

OBJECTIVE: To examine the intermodal agreement of Functional Independence Measure (FIM) ratings when obtained by two commonly used approaches: telephone interview and in-person assessment of functional performance. DESIGN: A random sample of 40 persons with hemiparesis was tested by two registered nurses trained in FIM definitions and telephone interview techniques. The two assessments occurred within 5 days of each other. The raters were blind to previous assessments. The administration of assessments was alternated to minimize bias and order effects. SETTING: All subjects were assessed at home, between 3 and 10 months after discharge from rehabilitation. PATIENTS: The criteria for inclusion were: (1) diagnosis of cerebral vascular accident (CVA); (2) completion of a minimum of 2 weeks in an acute rehabilitation program; (3) currently living at home; (4) living within a 30-mile radius of the hospital; and (5) cognitive and verbal skills adequate to complete a telephone interview. From a population of 103 patients, 40 subjects were randomly selected, 18 women and 22 men ranging in age from 37 to 90 years. MAIN OUTCOME MEASURES: The intermodal agreement between FIM ratings obtained by telephone interview and in-person assessment was examined using the intraclass correlation (ICC). FIM item scores were analyzed for agreement using the Kappa coefficient. The stability of the responses was determined by computing the coefficient of variation and plotting the data to visually examine the relationship between the two methods of administration. RESULTS: Data analysis revealed that there was no statistically significant difference (p > .05) between the two methods of administration for total FIM score. The total FIM ICC was .97. ICC values for FIM subscales ranged from .85 to .98, except for social cognition. Kappa scores for noncognitive items ranged from .49 (bowel movement) to .93 (grooming). The coefficient of variation computed to examine cognitive and communication items with reduced variability indicated good stability across all items. CONCLUSION: The results indicated good intermodal agreement for follow-up telephone assessment using the Functional Independence Measure. The findings were limited to persons with effective communication skills.

Setting air quality standards for carcinogens: an alternative to mathematical quantitative risk assessment--discussion paper.

1. It has been accepted in many countries that the regulation of ambient air quality should involve the use of health-based air quality standards. 2. Setting standards for air pollutants which are genotoxic carcinogens presents difficult problems to the regulator, in that the prediction of the effects on health of low levels of exposure is suspected to be inaccurate, and is not presently amenable to either experimental or epidemiological verification. 3. In some countries, techniques of Mathematical Quantitative Risk Assessment (MQRA) have been adopted to calculate acceptable levels of exposure to, or the unit risk factors for, genotoxic carcinogens. We regard these approaches as unsatisfactory. 4. An alternative approach, based upon a number of argued premises, a strategy which identifies decision points and the cautious application of uncertainty factors, is described.

Acceptance of in vitro studies by regulatory authorities.

There has been relatively little progress regarding the acceptance of in vitro tests by regulatory authorities since the second Practical In Vitro Toxicology Conference in 1989. Advances have been made in the international acceptance of the use of in vitro methods to identify compounds with mutagenic potential. The recognition, in international guidelines on skin and eye irritancy studies, of the need for a hierarchical approach, including the use of in vitro methods to screen out severe irritants, has also been welcome. The reasons for the relatively slow progress are considered. In the case of repeated-dose animal toxicity studies, these represent an effective broad-spectrum approach to identifying the general toxic effects and target organs. It will be difficult to design in vitro methods capable of mirroring the complex interactions seen in the whole animal or the multitudes of potential targets for toxic effects. In vitro studies may, however, be valuable in characterizing such effects once identified from the animal studies. Similar considerations apply to teratogenicity, where possible mechanisms include disturbances in placental function or in maternal metabolism. These examples illustrate the fairly substantial scientific obstacles that exist in some areas. The relatively rapid acceptance of mutagenicity studies was, to some extent, due to their single, underlying mechanism, namely, damage to DNA. In view of these problems, effort has concentrated on local effects such as skin and eye irritancy. Even here, the in vivo response is a complex series of reactions, and there is the assumption that a battery of in vitro tests will be needed. There have been difficulties in identifying the most promising combination of tests to subject to detailed validation. In addition, the number and identity of the 'reference' chemicals to be used and the comparative data (in vivo animal data or human data) needed has proved to be a matter of much debate. In addition to these difficulties, the need for international acceptance of the validation data has necessitated the adoption of a more international perspective. However, a large international study is now underway which, it is hoped, will lead to some real progress in the eye irritancy area.