Toxicology testing (often called “safety testing” or “product safety testing”) is an essential component of many industries, including the chemical industry, pharmaceuticals, and environmental science. It involves the evaluation of any potential health hazards posed by chemicals and other substances to humans, to other animals, and to the environment. This testing is performed during the development of new chemicals and pharmaceuticals to ensure their safety before they are released into the market where exposure could occur. As companies continuously develop new products, each new chemical substance requires safety testing. Within the Toxics Substances Control Act (TSCA) Chemical Substance Inventory, the EPA maintains a comprehensive inventory of the over 86,000 chemical substances manufactured, processed, or imported into the US. Any new substance must undergo safety testing to determine acceptable exposure limits before being added to this inventory.
The use of traditional mammalian animal models (mice, rats, rabbits, dogs, etc.) is still entrenched in the testing industry for modern preclinical studies of novel compounds or unique mixtures of compounds due to these models’ inherent similarities to human physiology, genetics, and anatomy. From 2019 to 2021, ~820,000 animals on average were used for testing in the US per year according to the USDA Animal and Plant Health Inspection Service. Aside from the myriad of related ethical issues, animal testing has several business-related downsides. Animal studies tend to be expensive due to the high costs of animal housing and care, the requirement for specialized personnel to conduct and interpret the studies, and the lengthy regulatory process involved in obtaining and maintaining the animals. In addition, results from animal studies take years to generate actionable results due to the natural timescale of traditional animal models’ lifespans. Together, the high cost and long timeline inherent to traditional animal studies have led stakeholders in the safety testing industry to seek more cost-effective and rapid methodologies.
To incentivize innovation in this area, the US Environmental Protection Agency (EPA) has enacted a directive to ban the use of animal studies in approvals of chemical entities by the year 2035 in response to growing public pressure to reduce the use of animals in safety testing. The EPA and other agencies along with industry partners with a focus on good stewardship have established working groups to promote the development of and evaluate new approach methodologies (NAMs) to fulfill safety testing requirements without the use of animals. Such NAMs include the study of in vitro models, computer-simulated in silico models, and other alternative-to-animal models.
C. elegans, a microscopic, translucent roundworm, has emerged as a key toxicology model in the realm of NAMs (Figure 1). The organism has been one of the most popular model organisms in the scientific research community for decades, providing insights into a wide range of biological processes with several studies leading to Nobel prizes. In addition to its strengths as a general model organism, C. elegans has a unique combination of ethical, practical, and biological traits that make it a particularly excellent model for toxicology. First, as a microscopic invertebrate, it is not subject to animal welfare regulation. From a practical standpoint, C. elegans excels as a model organism because of its short time to reproductive maturity (3 days), brief lifespan (2-3 weeks), and large brood size, making it easier, cheaper, and faster to grow in a laboratory environment than mammal models. The lifetime effects of test chemical exposure can be gauged in weeks for C. elegans as opposed to months in mammalian models.
In addition to its practical benefits, C. elegans has conserved genetic homology with humans, meaning that many of the genes and biological pathways in the worm are similar to those in humans. This makes it possible to study the effects of toxins on key biological processes in the worm and to extrapolate these results to humans. Another distinct advantage C. elegans has as a model compared to today’s mammalian models is the ease of studying specimens from genetically diverse backgrounds (Figure 2). Screening of compounds on worms of multiple genetic backgrounds results in toxicity endpoint data that can capture information about different genetic susceptibility factors than studies using inbred mammalian models. Such data on genetically diverse backgrounds more accurately simulate the effect of a compound on humans, who are ourselves genetically diverse.
Results of recent studies have bolstered confidence in C. elegans as a biological model for toxicology studies, suggesting that safety testing using C. elegans indeed predicts toxic response in higher mammalian animal models:
Despite its many advantages, C. elegans is not a perfect model for studying the effects of toxins on human health. It is rather unlikely that screens using solely C. elegans as a model could yield sufficiently detailed predictions of toxicology analyses in mammals to wholly replace safety testing in mammals. However, because of the study-proven conserved toxicity pathways and modes of toxic action between worms and humans, a C. elegans-based toxicology screen has immediate applications in the product safety testing industry.
Though use of traditional animal models in toxicology testing has long been the norm, but the ethical concerns, high costs, and slow pace of results have led to the development of NAMs. C. elegans, with its ethical and practical advantages, as well as its genetic homology with humans and diverse genetic background able to be maintained in a laboratory, has emerged as a promising model organism for toxicology. The use of C. elegans for toxicity screening can provide valuable data to support the safety of chemicals and pharmaceuticals, and studies have shown that results from C. elegans toxicity screening are highly correlated with those from traditional animal models. Its predictive power and advantages make it a valuable tool for early-stage toxicology studies, and it is likely to become increasingly important in the development of safer chemicals and pharmaceuticals.
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