The development of a Reference Chemical Potency List (RCPL), and its purpose, has been described previously. That original RCPL comprised 33 chemicals, of varying skin sensitising activity, for each of which a discrete Potency Value (PV) was derived, based upon the best available human and/or animal (local lymph node assay) data. The purpose of the RCPL was to provide a reliable tool that would facilitate evaluation of the ability of New Approach Methodologies (NAMs) to measure skin sensitising potency. We here report the construction of an extended RCPL with 77 additional chemicals by applying the weight of evidence framework used previously. This extended RCPL adheres to the salient features of the original database. These comprise a focus largely on fragrance chemicals, provision of a wide range of chemical structures and of skin sensitising potency, the inclusion of both direct and indirect (pre- and pro-) haptens, the exclusion of NAMs data for the derivation of PVs, and avoidance of the use of potency categories for the classification of chemicals. It is anticipated that this extended RCPL will provide a more powerful database with which to assess the strengths and weakness of recently developed NAMs in the measurement of skin sensitising potency.

This review addresses the need for a framework to increase the consistency, objectivity and transparency in the regulatory assessment of respiratory sensitisers and associated uncertainties. Principal issues are considered and illustrated through a case study (with methyl methacrylate). In the absence of test methods validated for regulatory use, formal documentation of the weight-of-evidence for hazard classification both at the level of integration of individual studies within lines of evidence and across a broad range of data streams was agreed to be critical for such a framework. An integrated approach is proposed to include not only occupational studies and clinical evidence for the regulatory assessment of respiratory sensitisers, but also information on structure and physical and chemical factors, predictive approaches such as structure activity analysis and in vitro and in vivo mechanistic and toxicokinetic findings. A weight-of-evidence protocol, incorporating integration of these sources of data based on predefined considerations, would contribute to transparency and consistency in the outcome of the assessment. In those cases where a decision may need to be taken on the basis of occupational findings alone, conclusions should be based on transparent weighting of relevant data on the observed prevalence of occupational asthma in various studies taking into account all relevant information including the range and nature of workplace exposures to the substance of interest, co-exposure to other chemicals and study quality.

A fully integrated Chemicals Strategy for Sustainability (CSS) in respect of chemicals is crucial and must include: • An objective evaluation of the present situation including impacts of 'chemicals of concern' throughout their life cycle, that incorporates sustainability issues. • A framework that facilitates innovation of chemistry-based approaches to tackle each of the key sustainability issues. The EU CSS only addresses adverse impacts and mainly focusses on one aspect of risk assessment, the hazard to humans from individual industrial chemicals. The proposal removes consideration of the nature and amount of exposure, which is a critical determinant of risk. It can be presumed that this is solely to simplify, and hence speed up, regulatory decisions thereby enabling more chemicals to be assessed. The linkage of this proposed approach to address any of the major sustainability issues, such as environmental pollutants is obscure. For example, the well-recognised environmental problems caused by polymers such as plastics are not considered. The proposed change in the assessment methodology lacks any scientific justification and fails to address the sustainability issues the EU and the rest of the world are facing. The authors critically discuss a comprehensive innovative evaluation methodology for the impact of chemicals.

BACKGROUND:Evaluating and managing exposures to chemical, physical and biological stressors, which frequently interplay with psychological stressors as well as social and behavioural aspects, is crucial for protecting human and environmental health and transitioning towards a sustainable future. Advances in our understanding of exposure rely on input from well-trained exposure scientists. However, no education programmes in Europe are currently explicitly dedicated to cover the broader range of exposure science approaches, applications, stressors and receptors.OBJECTIVE:To address this challenge, a curriculum is needed that yields credible, well-defined career pathways in exposure science.METHODS:Needs and conditions for advancing exposure science education in Europe were identified. As a starting point for a way forward, harmonised learning outcomes for exposure science were defined at each level of the European Qualifications Framework. The course programme coordinators were recruited for three varying courses, with respect to the course level and the proportion of the curriculum dedicated to exposure science. These courses were assessed via our systematic course review procedure. Finally, strategic objectives and actions are proposed to build exposure science education programmes.RESULTS:The ISES Europe 'Education, Training and Communication' expert working group developed a framework for creating a viable exposure science curriculum. Harmonised learning outcomes were structured under eight learning levels, categorised by knowledge, skills and competence. Illustrative case studies demonstrated how education providers integrated these learning outcomes for their educational context and aligned the overall exposure science curriculum.CONCLUSIONS:The international recognition and adoption of exposure science education will enable advances in addressing global exposure science challenges for various stressors, from behavioural aspects from individual to population scale, and effective communication between exposure scientists and relevant stakeholders and policy makers, as part of the European Exposure Science Strategy 2020-2030.

In 2008, a proposal for assessing the risk of induction of skin sensitization to fragrance materials Quantitative Risk Assessment 1 (QRA1) was published. This was implemented for setting maximum limits for fragrance materials in consumer products. However, there was no formal validation or empirical verification after implementation. Additionally, concerns remained that QRA1 did not incorporate aggregate exposure from multiple product use and included assumptions, e.g. safety assessment factors (SAFs), that had not been critically reviewed. Accordingly, a review was undertaken, including detailed re-evaluation of each SAF together with development of an approach for estimating aggregate exposure of the skin to a potential fragrance allergen. This revision of QRA1, termed QRA2, provides an improved method for establishing safe levels for sensitizing fragrance materials in multiple products to limit the risk of induction of contact allergy. The use of alternative non-animal methods is not within the scope of this paper. Ultimately, only longitudinal clinical studies can verify the utility of QRA2 as a tool for the prevention of contact allergy to fragrance materials.

A quantitative weight of evidence (QWoE) methodology was developed to assess confidence in postulated mode(s) of action for adverse effects in animal toxicity studies. The QWoE is appropriate for assessing adverse effects as relevant endpoints for classification and labeling purposes. The methodology involves definition of mode of actions and scoring supporting data for all key steps using predefined criteria for quality and relevance/strength of effects. Scores for all key steps are summarized, and the summary score is compared to the maximal achievable score for the mode of action. The ratio of the summary score to the maximal achievable scores gives an indication of confidence in a specific mode of action in animals. The mode of action in animals with highest confidence is then taken forward to assess appropriateness to humans. If one of the key steps cannot occur in humans, the mode of action is not relevant to humans. The methodology developed is applied to four case studies.

Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized. From this review, several gaps were identified that need to be addressed before use of these nonclinical models can be considered a viable option to predict the relative risk for SIB. Other future directions that may compliment these nonclinical approaches, including the use of selectively-bred or genetically-modified rodent models, transgenic models, gene expression profiling, and biomarker analysis, are discussed. This article was developed with the support of the DruSafe Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org).

Hazard assessment of chemicals usually applies narrative assessments with a number of weaknesses. Therefore, application of weight of evidence (WoE) approaches are often mandated but guidance to perform a WoE assessment is lacking. This manuscript describes a quantitative WoE (QWoE) assessment for reproductive toxicity data and its application for classification and labeling (C&L). Because C&L criteria are based on animal studies, the scope is restricted to animal toxicity data. The QWoE methodology utilizes numerical scoring sheets to assess reliability of a publication and the toxicological relevance of reported effects. Scores are given for fourteen quality aspects, best practice receives the highest score. The relevance/effects scores (0 to four) are adjusted to the key elements of the toxic response for the endpoint and include weighting factors for effects on different levels of the biological organization. The relevance/effects scores are then assessed against the criteria dose-response, magnitude and persistence of effects, consistency of observations with the hypothesis, and relation of effects to human disease. The quality/reliability scores and the relevance/effect scores are then multiplied to give a numerical strength of evidence for adverse effects. This total score is then used to assign the chemical to the different classes employed in classification.

Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility.

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply. Current “background” (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase. However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association. Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms. Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized.

It is the ultimate goal of the intended REACH process (Registration, Evaluation and Authorization of Chemicals) of the European Union to identify substances of hazardous properties and to evaluate the risks of human and environmental exposure. During the last few months there has been a controversial discussion as to what extent in vitro studies and consideration of structure activity relationship provide sufficient information to waive repeated exposure studies. Industry as well as certain regulatory agencies or NGOs support this approach and propose that repeated dose studies may only be required beyond 100 t/a. From a toxicological point of view it has to be stressed that this discussion primarily considers the cost reduction and protection of animals, whereas protection of human health and the environment are secondary. In vitro studies only allow identification of specific hazardous properties which can be detected by the specific test system. Moreover, appropriate information on the dose response of adverse effects, identification of thresholds and NOELs that are essential for risk characterization cannot be obtained from these studies. Consequently, identification of all relevant hazardous properties and endpoints of adverse effects can only be determined in the intact animal by repeated dose studies such as 28-day or 90-day studies. In the absence of such information the hazard identification is incomplete and there is no basis for appropriate risk assessment of human exposure. Thus, any waiving of repeated dose studies in animals bears the probability of unforeseen effects in case of acute or continuous human exposure. From this the undersigning European Toxicologists conclude: 1. The intention of REACH is to identify hazardous properties in order that a reliable risk assessment can be made and measures taken to deal with chemicals posing a significant risk. 2. The recent debate has centered on ways in which the well established in vivo methods for risk assessment can be bypassed. 3. The evidence that the available alternatives would support such replacement is weak. Progress to improve their value for risk assessment purposes is bound to be slow because the issues are very complex. As a group of European Toxicologists we strongly support the need for more research support in these areas, but we believe that over claims for progress is damaging their development. 4. Under the circumstances only two options are available: to reduce very substantially the estimation of hazard and risk with inevitable adverse consequences for human health and environmental protection, or to continue the existing methods until properly validated new methods are available.

14 Baan, R. A., Schoen, M. A, Zaalberg, O. B. and Lohman, P. H. M. (1982) in Mutagens in our environment (Proceedings of the 12th annual EEMS meeting, Helsinki, Finland), pp. 111-124, Alan R. Liss, New York 15 Pereira, M. A., Lin, L. H. C. and Chang, L. W. (1981) Toxicol. Appl. Pharmacol. 60, 472-478 16 Kriek, E. (1972) Biochem. Biophys. Acta 355, 77-203 17 Adamson, R. H. and Sieber, S. M. (1977) in Origins of human cancer (Hiatt, H. H., Watson, J. D. and Winsten, J. A., eds), pp. 429-443, Cold Spring Harbor Laboratory 18 Muysken-Schoen, M. A., Baan, R. A. and Lohman, P. H. M. (1985) Carcinogenesis 6, 999-1004 19 Scribner, N. K., Woodworth, B., Ford, G. P. and Scribner, J. D. (1980) Carcinogenesis 1, 715 20 Glatt, H. R. and Oesch, F. (1977) Arch. Toxicol. 39, 87 21 Wright, A. S. (1980) Mutat Res. 75, 215-241 22 Sobels, F. H. (1980) Arch. Toxicol. 46, 21 23 Lohman, P. H.M., Jansen, J.D. and Baan, R.A. (1984) in Monitoring Human Exposure to Carcinogenic and Mutagenic Agents (Berlin, H., Vainio, H. and Draper, M., eds), pp. 259-277, IARC Scientific Publications, vol. 59, IARC, Lyon, France 24 Abbondandolo, A., Dogliotti, E., Lohman, P. H. M. and Berends, F. (1982) Mutat. Res. 92, 361-377 $11

A primary rat hepatocyte culture system has been developed for the study of peroxisome proliferation. Maximal induction of peroxisomal activity requires supplementation of the culture medium with hydrocortisone. The addition of clofibric acid (0.01–1 mM), mono-(2-ethylhexyl)phthalate (0.01–0.5 mM) and trichloroacetic acid (0.1–5 mM) to cultured rat hepatocytes resulted in a time- and dose-related increase in CN- insensitive palmitoyl CoA oxidation (maximal increases: 27-, 15.5-, and 5-fold respectively) and mitochondrial α-glycerophosphate dehydrogenase activity (maximal increases: 7.3-, 5.8-, and 1.6-fold respectively). Electron microscopic examination revealed smooth endoplasmic reticulum proliferation and morphometric analysis indicated an increase in fractional peroxisomal volume of X 8 and X 4 for clofibric acid (1 mM) and trichloroacetic acid (2.5 mM), respectively. SDS-PAGE of cell homogenates revealed an intensified protein band of mol. wt. 76–78,000. The induction of peroxisomal β-oxidation by clofibric acid was elevated from 9- to 12-fold by supplementation of the medium with l-carnitine (2mM).

The rate of growth of normal human skin fibroblasts was inhibited in a dose related, reversible, fashion by practolol (N-4-(2-hydroxy)-3 (1-methyl)-aminopropoxyphenylacetamine) (ID50 1.35 ± 0.14 x 10-3M), propranolol (1-(isopropylamino)-3(1-naphthyl-oxy)-2-propranolol) (ID50 0.145 ± 0.02 x 10-3M) and paracetamol (N-(4-hydroxyphenyl) acetamide) (ID50 0.85 ± 0.2 x 10-3M). Skin fibroblasts isolated from a psoriasis patient were more sensitive towards practolol (ID50 0.48 ± 0.14 x 10-3M) and propranolol (ID50 0.032 ± 0.002 x 10-3M), but less sensitive towards paracetamol (ID50 1.3 ± 0.07 x 10-3M). In vitro generated metabolites of practolol, using normal or Arochlor 1254-pretreated hamster liver preparations, and structural analogues of practolol had no effect upon the growth of either cell type.

It is timely to consider critically our present approach to toxicity testing. On the one hand there is considerable public concern over the number of chemicals for which inadequate toxicological information exists and to which man is significantly exposed. Estimates that 30,000–50,000 chemicals are in this category have been made (e.g. Miller, 1978). In addition, several hundred new chemicals are being introduced each year which require some form of toxicological investigation. On the other hand there are mounting economic and moral pressures to change the testing methods that are currently employed.

Conference Article| August 01 1982 Accumulation of lipid-rich lysosomes in the livers and kidneys of animals treated with hypolipidaemic agents SHIRLEY C. PRICE; SHIRLEY C. PRICE *Robens Institute of Industrial and Environmental Health, Safety and University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar RICHARD H. HINTON; RICHARD H. HINTON *Robens Institute of Industrial and Environmental Health, Safety and University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar DEREK E. HALL; DEREK E. HALL †Department of Biochemistry, University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar PAUL GRASSO; PAUL GRASSO †Group Occupational Health Centre, BP Research Centre, Sunbury, Middx., U.K. Search for other works by this author on: This Site PubMed Google Scholar JAMES W. BRIDGES JAMES W. BRIDGES *Robens Institute of Industrial and Environmental Health, Safety and University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8752 Print ISSN: 0300-5127 © 1982 Biochemical Society1982 Biochem Soc Trans (1982) 10 (4): 244. https://doi.org/10.1042/bst0100244 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation SHIRLEY C. PRICE, RICHARD H. HINTON, DEREK E. HALL, PAUL GRASSO, JAMES W. BRIDGES; Accumulation of lipid-rich lysosomes in the livers and kidneys of animals treated with hypolipidaemic agents. Biochem Soc Trans 1 August 1982; 10 (4): 244. doi: https://doi.org/10.1042/bst0100244 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1982 Biochemical Society1982 Article PDF first page preview Close Modal You do not currently have access to this content.