Alternative methods go green! Green toxicology as a sustainable approach for assessing chemical safety and designing safer chemicals

Green toxicology is marching chemistry into the 21st century. This emerging framework will transform how chemical safety is evaluated by incorporating evaluation of the hazards, exposures, and risks associated with chemicals into early product development in a way that minimizes adverse impacts on human and environmental health. The goal is to minimize toxic threats across entire supply chains through smarter designs and policies. Traditional animal testing methods are replaced by faster, cutting-edge innovations like organs-on-chips and artificial intelligence predictive models that are also more cost-effective. Core principles of green toxicology include utilizing alternative test methods, applying the precautionary principle, considering lifetime impacts, and emphasizing risk prevention over reaction. This paper provides an overview of these foundational concepts and describes current initiatives and future opportunities to advance the adoption of green toxicology approaches. Chal-lenges and limitations are also discussed. Green shoots are emerging with governments offering carrots like the European Green Deal to nudge industry. Noteworthy, animal rights and environ-mental groups have different ideas about the needs for testing and their consequences for animal use. Green toxicology represents the way forward to support both these societal needs with sufficient throughput and human relevance for hazard information and minimal animal suffering. Green toxi-cology thus sets the stage to synergize human health and ecological values. Overall, the integration of green chemistry and toxicology has potential to profoundly shift how chemical risks are evaluated and managed to achieve safety goals in a more ethical, ecologically-conscious manner.

Green toxicology aims to make chemicals safer by design. It focuses on preventing toxicity issues early during development instead of testing after products are developed. Green toxicology uses modern non-animal methods like computer models and lab tests with human cells to predict if chem­icals could be hazardous. Benefits are faster results, lower costs, and less animal testing. The principles of green toxicology include using alternative tests, applying caution even with uncertain data, con­sidering lifetime impacts across global supply chains, and emphasizing prevention over reaction. The article highlights European and US policy efforts to spur sustainable chemistry innovation which will necessitate greener approaches to assess new materials and drive adoption. Overall, green toxi­cology seeks to integrate safer design concepts so that human and environmental health are valued equally with functionality and profit. This alignment promises safer, ethical products but faces chal­lenges around validating new methods and overcoming institutional resistance to change.

4.2 million and counting The animal toll for REACH systemic toxicity studies.

The EU's chemicals regulation, REACH, requires that most chemicals in the EU be evaluated for human health and ecosystem risks, with a mandate to minimize use of animal tests for these evaluations. The REACH process has been ongoing since about 2008, but a calculation of the resulting animal use is not publicly available. For this reason, we have undertaken a count of animals used for REACH. With EU legislators set to consider REACH revisions that could expand animal testing, we are releasing results for test categories counted to date: reproductive toxicity tests, developmental toxicity tests, and repeat-ed-dose toxicity tests for human health. The total animal count as of December 2022 for these categories is about 2.9 million. Additional tests involving about 1.3 million animals are currently required by a final proposal authorization or compliance check but not yet completed. The total, 4.2 million, for just these three test categories exceeds the original European Com-mission forecast of 2.6 million for all REACH tests. The difference is primarily because the European Commission estimate excluded offspring, which are most of the animals used for REACH. Other reasons for the difference are extra animals included in tests to ensure sufficient survive to meet the minimum test requirement; dose range-finding tests; extra test animal groups, e.g., for recovery analysis; and a high rejection rate of read-across studies. Given higher than forecast animal use, the upcoming debate on proposed REACH revisions is an opportunity to refocus on reducing animal numbers in keeping with the REACH mandate.

Continuing animal tests on cosmetic ingredients for REACH in the EU

EU cosmetic ingredients are governed by two regulations that conflict. Regulation EC 1223/2009, the Cosmetic Regulation, bans in vivo (animal) testing for cosmetic product safety assessments, including both final products and ingredients. At the same time, the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation can impose in vivo testing of those same ingredients under its chemical testing requirements. Here, we examined REACH dossiers for chemicals for which the only reported use is cosmetics to determine the extent of new in vivo testing caused by REACH. We found the REACH database has 3,206 chemical dossiers with cosmetics as a reported use. Of these, 419 report cosmetics as the only use, and 63 of these have in vivo tests completed after the Cosmetic Regulation ban on in vivo testing. Registrants largely used alternative, non-animal methods to evaluate ingredients for REACH, but some still conducted new in vivo tests to comply with REACH requirements for toxicity data and worker safety assessments. In some cases, ECHA, the agency that evaluates REACH dossiers, rejected registrants' alternative methods as insufficient and required new in vivo tests. As ECHA continues to evaluate dossiers, more requests for in vivo tests are likely. REACH tests on cosmetic ingredients appear only as "industrial chemicals legislation" tests in EU reports. Given the importance to consumers and the cosmetic industry of having cosmetics free of animal testing, the public should be made aware of REACH testing until the conflict between the regulations is resolved.

Safety evaluations under the proposed US Safe Cosmetics and Personal Care Products Act of 2013: animal use and cost estimates.

The proposed Safe Cosmetics and Personal Care Products Act of 2013 calls for a new evaluation program for cosmetic ingredients in the US, with the new assessments initially dependent on expanded animal testing. This paper considers possible testing scenarios under the proposed Act and estimates the number of test animals and cost under each scenario. It focuses on the impact for the first 10 years of testing, the period of greatest impact on animals and costs. The analysis suggests the first 10 years of testing under the Act could evaluate, at most, about 50% of ingredients used in cosmetics. Testing during this period would cost about $ 1.7-$ 9 billion and 1-11.5 million animals. By test year 10, alternative, high-throughput test methods under development are expected to be available, replacing animal testing and allowing rapid evaluation of all ingredients. Given the high cost in dollars and animal lives of the first 10 years for only about half of ingredients, a better choice may be to accelerate development of high-throughput methods. This would allow evaluation of 100% of cosmetic ingredients before year 10 at lower cost and without animal testing.