January is National Birth Defect Prevention Month, and Battelle is proud to be doing our part. The Battelle Developmental and Reproductive Toxicology (DART) team is working to understand the effects of household and industrial chemicals, environmental toxins and pharmaceuticals on pregnant mothers and developing fetuses.
Birth defects are a leading cause of infant mortality in the U.S.; according to the Centers for Disease Control and Prevention (CDC), they account for 1 in 5 infant deaths. While the causes range from genetic mutations to viruses such as Zika, maternal exposure to drugs or toxins before or during pregnancy remains a significant risk factor for fetal abnormalities. DART studies shed light on these exposure risks as well as longer-term impacts on the reproductive system and development of future offspring.
Why DART Matters
DART studies are conducted to ensure the safety of new life-saving drugs before they go on the market. They are also used to determine the safety of pesticides and other household or industrial chemicals. Results of these studies are used to develop safety guidelines to reduce exposure risks for different populations, including pregnant women, infants and young children.
Many of these chemicals are already in wide use and bring significant benefits to people, from pesticides that protect crops from destructive insects to antimicrobial cleaners that prevent the spread of dangerous diseases. According to the National Toxicology Program (NTP), more than 80,000 chemicals are registered in the U.S. for use in personal care products, food additives, lawn care products, prescription drugs, household cleaners and industrial applications. While most are considered safe, there is still much that we do not know about how many of these chemicals impact human health and the environment.
This is especially true when it comes to developmental and reproductive effects. Many drugs and chemicals that are considered safe for adults have significant impacts on vulnerable subpopulations including pregnant mothers, developing fetuses, infants and young children. They can also cause damage to the reproductive system that can lead to infertility or abnormalities in future offspring and even impact future generations.
NTP, a multi-agency program led by The National Institute of Environmental Health Sciences (NIEHS), was launched in 1978 to fill in these knowledge gaps and improve safety recommendations for chemicals and drugs. DART studies are an important part of their overall research program. Battelle has worked with NTP for more than 30 years on numerous toxicology studies. Over the last few years, we have added new DART capabilities and expertise to support NTP’s increased focus on this specialized area of toxicology.
Trends in reproductive health over the last several decades point to the importance of DART research. Since the 1970s, the U.S. has seen significant increases in rates of testicular cancer, breast cancer and hypospadias (a congenital malformation of the urethra in males). At the same time, sperm counts for men and boys have declined dramatically worldwide. The specific causes of these changes are unknown. DART studies are needed to determine whether exposure to specific drugs or chemicals is related to these and other reproductive and developmental effects.
What DART Studies Tell Us
Different types of studies are used to evaluate different aspects of reproduction and development. Generally, DART studies can be divided into two types, which can sometimes be combined.
- Developmental toxicity focuses on pre-natal development of the embryo or fetus. Toxicity may manifest as death of the embryo or fetus, abnormal development or birth defects or retardation of normal growth patterns.
- Reproductive toxicity looks at all aspects of fertility. This includes the reproductive cycle, sexual behavior, gamete (sperm or egg) production and transport, fertility (including sperm quality and quantity), pregnancy outcomes, gestation, childbirth, lactation and maternal behavior. These studies also examine postnatal survival, growth and development of offspring. Some studies look at multiple generations to detect heritable effects.
Toxicology studies use animal models to evaluate adverse effects on the reproductive system. Studies must be carefully designed with appropriate exposure routes (e.g. oral, inhalation or dermal) and dosages to provide data that is useful for predicting human exposure effects. Studies must also be conducted following various test guidelines to ensure ethical treatment of laboratory animal species.
Regulatory Requirements for DART Studies
In the U.S., the Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) have established guidelines for DART studies required for product registration and approval. Similar regulations are in place in the European Union (EU) and many other regions around the world. Companies must present data from DART studies conducted per applicable regulatory guidelines in order to market and use their products in these countries.
Pharmaceuticals: In the U.S., the FDA approves pharmaceuticals before they can be marketed. The toxicity tests that are required in the U.S. are dictated by test guidelines put forth by the International Conference on Harmonization (ICH).
Three DART tests are required for small molecule pharmaceuticals: Embryo-Fetal Development (EFD), Fertility and Early Embryonic Development (FEED) and a Pre- and Postnatal Development study (PPN). Combination studies may be performed to reduce the number of animals needed and to obtain results more quickly. (This should be decided on a case-by-case basis, as it may not be appropriate for a given drug.) For large molecule biopharmaceuticals, such as vaccines and proteins, other laboratory animal species and study designs may used.
Pesticides and Industrial Chemicals: Pesticides and industrial chemicals must also undergo DART testing to detect toxicity to the reproductive system, including prenatal and postnatal development of the offspring. In the U.S., the EPA requires DART testing for product registration of pesticides. For industrial chemicals, testing requirements are regulated by the EPA’s Toxic Substance Control Act (TSCA). The EU has similar DART testing requirements for registration of pesticides and industrial chemicals, which are described in the test guidelines put forth by the Organization for Economic Cooperation and Development (OECD). Required DART studies depend on the chemical substance and its intended use and may include developmental toxicity, one- and two-generation reproductive toxicity studies, the extended one-generation reproduction study or reproductive screening tests.
The Future of DART Research
As we understand more about the potential for damage to the reproductive system and to developing fetuses and young children, continued DART research is more important than ever. DART studies conducted at Battelle are helping to illuminate the exposure risks and mechanisms for developmental and reproductive toxicity for a wide range of chemicals and drugs.
While much progress has been made in defining the development and reproductive effects of regulated drugs and everyday chemicals, there are still many open questions for the industry to address. Future avenues of research for the industry may include examining the health effects of prenatal exposure on adult diseases (e.g. diabetes, obesity, cardiovascular disease) and studying the safety of over-the-counter dietary supplements and herbal medicines, which are not currently regulated by the FDA. Work is also needed to develop alternative models for DART testing. As new questions arise, the Battelle DART team will be working to find the answers.