scholarly journals Role of epidemiology in risk assessment: a case study of five ortho-phthalates

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Maricel V. Maffini ◽  
Birgit Geueke ◽  
Ksenia Groh ◽  
Bethanie Carney Almroth ◽  
Jane Muncke
Keyword(s):  
Risk Assessment ◽  
Health Outcomes ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Epidemiological Studies ◽  
Animal Testing ◽  
Environmental Chemical ◽  
Regulatory Toxicology ◽  
Chemical Risk Assessment

Abstract Background The association between environmental chemical exposures and chronic diseases is of increasing concern. Chemical risk assessment relies heavily on pre-market toxicity testing to identify safe levels of exposure, often known as reference doses (RfD), expected to be protective of human health. Although some RfDs have been reassessed in light of new hazard information, it is not a common practice. Continuous surveillance of animal and human data, both in terms of exposures and associated health outcomes, could provide valuable information to risk assessors and regulators. Using ortho-phthalates as case study, we asked whether RfDs deduced from male reproductive toxicity studies and set by traditional regulatory toxicology approaches sufficiently protect the population for other health outcomes. Methods We searched for epidemiological studies on benzyl butyl phthalate (BBP), diisobutyl phthalate (DIBP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), and bis(2-ethylhexyl) phthalate (DEHP). Data were extracted from studies where any of the five chemicals or their metabolites were measured and showed a statistically significant association with a health outcome; 38 studies met the criteria. We estimated intake for each phthalate from urinary metabolite concentration and compared estimated intake ranges associated with health endpoints to each phthalate’s RfD. Result For DBP, DIBP, and BBP, the estimated intake ranges significantly associated with health endpoints were all below their individual RfDs. For DEHP, the intake range included associations at levels both below and above its RfD. For DCHP, no relevant studies could be identified. The significantly affected endpoints revealed by our analysis include metabolic, neurodevelopmental and behavioral disorders, obesity, and changes in hormone levels. Most of these conditions are not routinely evaluated in animal testing employed in regulatory toxicology. Conclusion We conclude that for DBP, DIBP, BBP, and DEHP current RfDs estimated based on male reproductive toxicity may not be sufficiently protective of other health effects. Thus, a new approach is needed where post-market exposures, epidemiological and clinical data are systematically reviewed to ensure adequate health protection.

Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1) ◽  
pp. 65-80 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Endocrine Disruption ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME conducted a research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.

Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 123-138 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Endocrine Disruption ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME conducted a research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.

scholarly journals Chemical risk assessment based on in vitro and human biomonitoring data: A case study on thyroid toxicants

2019 ◽  
Vol 15 ◽  
pp. 8-17 ◽  
Author(s):  
Hanna K.L. Johansson ◽  
Julie Boberg ◽  
Marianne Dybdahl ◽  
Marta Axelstad ◽  
Anne Marie Vinggaard
Keyword(s):  
Risk Assessment ◽  
Human Biomonitoring ◽  
Chemical Risk ◽  
Chemical Risk Assessment

scholarly journals Chemical monitoring of Swedish coastal waters indicates common exceedances of environmental thresholds, both for individual substances as well as their mixtures

2017 ◽  
Author(s):  
Mikael B Gustavsson ◽  
Jörgen Magnér ◽  
Bethanie Carney Almroth ◽  
Martin K Eriksson ◽  
Joachim Sturve ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Concentration Addition ◽  
Chemical Pollution ◽  
Chemical Contamination ◽  
Total Risk ◽  
Environmental Chemical ◽  
Swedish West Coast ◽  
Chemical Monitoring ◽  
Chemical Risk Assessment ◽  
The Individual

Chemical pollution was monitored and assessed along the Swedish west coast. 62 of 172 analyzed organic chemicals were detected in the water phase of at least one of five monitored sites. A Concentration Addition based screening-level risk assessment indicates that all sites are put at risk from chemical contamination, with total risk quotients between 2 and 9. Only at one site did none of the individual chemicals exceeded its individual environmental threshold (PNEC, EQS). The monitoring data thus demonstrate a widespread blanket of diffuse pollution, with no clear trends amongst sites. Further issues critical for the environmental chemical risk assessment include the challenges to achieve sufficiently low levels of detection especially for hormones and cybermethrin (a pyrethroid insecticide), the appropriate consideration of non-detects and the limited availability of reliable PNECs and EQS values.

scholarly journals A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

2020 ◽  
Vol 176 (1) ◽  
pp. 236-252 ◽  
Author(s):  
Maria T Baltazar ◽  
Sophie Cable ◽  
Paul L Carmichael ◽  
Richard Cubberley ◽  
Tom Cull ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Biological Effects ◽  
In Vitro Assays ◽  
Next Generation ◽  
Animal Testing ◽  
Immunomodulatory Effects ◽  
Margin Of Safety

Abstract Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 and BioMap Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure to calculate a margin of safety with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with margin of safety higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer-relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modeling and in vitro bioactivity data, to reach a safety decision without animal data.

Integrated Decision-tree Testing Strategies for Environmental Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 29-42 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Aquatic Toxicity ◽  
Toxicity Testing ◽  
Threshold Concentration ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME recently conducted a research project sponsored by Defra on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for using alternative methods (both in vitro and in silico) for environmental (aquatic) toxicity testing. The manuscript reviews tests based on fish cells and cell lines, fish embryos, lower organisms, and the many expert systems and QSARs for aquatic toxicity testing. Ways in which reduction and refinement measures can be used are also discussed, including the Upper Threshold Concentration — Step Down (UTC) approach, which has recently been retrospectively validated by ECVAM and subsequently endorsed by the ECVAM Scientific Advisory Committee (ESAC). It is hoped that the application of this approach could reduce the number of fish used in acute toxicity studies by around 65–70%. Decision-tree style integrated testing strategies are also proposed for acute aquatic toxicity and chronic toxicity (including bioaccumulation), followed by a number of recommendations for the future facilitation of aquatic toxicity testing with respect to environmental risk assessment.

scholarly journals Role of Risk of Bias in Systematic Review for Chemical Risk Assessment: A Case Study in Understanding the Relationship Between Congenital Heart Defects and Exposures to Trichloroethylene

2018 ◽  
Vol 37 (2) ◽  
pp. 125-143 ◽  
Author(s):  
Daniele Wikoff ◽  
Jon D. Urban ◽  
Seneca Harvey ◽  
Laurie C. Haws
Keyword(s):  
Risk Assessment ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Risk Of Bias ◽  
Assessment Process ◽  
Chemical Risk ◽  
Chemical Risk Assessment

The National Academy of Science has recommended that a risk of bias (RoB; credibility of the link between exposure and outcome) assessment be conducted on studies that are used as primary data sources for hazard identification and dose–response assessment. Few applications of such have been conducted. Using trichloroethylene and congenital heart defects (CHDs) as a case study, we explore the role of RoB in chemical risk assessment using the National Toxicology Program’s Office of Health Assessment and Translation RoB tool. Selected questions were tailored to evaluation of CHD and then applied to 12 experimental animal studies and 9 epidemiological studies. Results demonstrated that the inconsistent findings of a single animal study were likely explained by the limitations in study design assessed via RoB (eg, lack of concurrent controls, unvalidated method for assessing outcome, unreliable statistical methods, etc). Such limitations considered in the context of the body of evidence render the study not sufficiently reliable for the development of toxicity reference values. The case study highlights the utility of RoB as part of a robust risk assessment process and specifically demonstrates the role RoB can play in objectively selecting candidate data sets to develop toxicity values.

Reproductive Toxicity Testing: Evaluating and Developing New Testing Systems

1985 ◽  
Vol 4 (2) ◽  
pp. 163-171 ◽  
Author(s):  
J. C. Lamb
Keyword(s):  
Environmental Protection Agency ◽  
Food Additives ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Reproductive Function ◽  
Test System ◽  
Toxic Substances ◽  
Animal Testing ◽  
In Vitro Techniques

Reproductive toxicity testing systems are used by national and international regulatory agencies. Protocols have not been standardized between agencies or even within certain agencies. Although there have been efforts at standardization, a certain amount of the differences between testing protocols is a reflection of the needs of the particular agency. New developments in in vitro techniques might lead to new test systems, but reproductive function is dependent upon the interaction of various cells and organs that cannot presently be copied in the test tube; this makes whole-animal testing systems a necessity. The present whole-animal models used by the Food and Drug Administration include the 3 segment reproduction studies used for testing drug safety and the multigeneration studies used for food additives. The Environmental Protection Agency has adopted 2 similar versions of a 2-generation study for the Office of Pesticide Programs and the Office of Toxic Substances. The National Toxicology Program, although not a regulatory agency, has taken a prominent role in reproductive toxicity testing, test system development, and test system evaluation. A new testing system, Fertility Assessment by Continuous Breeding (FACB), is currently being studied as a cost-effective and reliable alternative test system. The FACB protocol houses male and female mice as breeding pairs and removes offspring as soon as they are born during the first 14 weeks to allow continuous mating. Each breeding pair normally has up to 5 litters, and the last litter is saved to evaluate the second generation. The efficiency, reliability, and expense of the protocol are being compared to the existing testing systems.

Assuring Consumer Safety without Animal Testing: A Feasibility Case Study for Skin Sensitisation

2008 ◽  
Vol 36 (5) ◽  
pp. 557-568 ◽  
Author(s):  
Gavin Maxwell ◽  
Maja Aleksic ◽  
Aynur Aptula ◽  
Paul Carmichael ◽  
Julia Fentem ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Conceptual Framework ◽  
New Technologies ◽  
The European Union ◽  
Animal Testing ◽  
Safety Risk ◽  
Skin Sensitisation ◽  
Consumer Safety

Allergic Contact Dermatitis (ACD; chemical-induced skin sensitisation) represents a key consumer safety endpoint for the cosmetics industry. At present, animal tests (predominantly the mouse Local Lymph Node Assay) are used to generate skin sensitisation hazard data for use in consumer safety risk assessments. An animal testing ban on chemicals to be used in cosmetics will come into effect in the European Union (EU) from March 2009. This animal testing ban is also linked to an EU marketing ban on products containing any ingredients that have been subsequently tested in animals, from March 2009 or March 2013, depending on the toxicological endpoint of concern. Consequently, the testing of cosmetic ingredients in animals for their potential to induce skin sensitisation will be subject to an EU marketing ban, from March 2013 onwards. Our conceptual framework and strategy to deliver a non-animal approach to consumer safety risk assessment can be summarised as an evaluation of new technologies (e.g. ‘omics’, informatics), leading to the development of new non-animal ( in silico and in vitro) predictive models for the generation and interpretation of new forms of hazard characterisation data, followed by the development of new risk assessment approaches to integrate these new forms of data and information in the context of human exposure. Following the principles of the conceptual framework, we have been investigating existing and developing new technologies, models and approaches, in order to explore the feasibility of delivering consumer safety risk assessment decisions in the absence of new animal data. We present here our progress in implementing this conceptual framework, with the skin sensitisation endpoint used as a case study.

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