title: Alternative Models of Developmental and Reproductive Toxicity in Pharmaceutical Risk Assessment and the 3Rs.
abstract: In the pharmaceutical industry, preclinical developmental and reproductive toxicity studies are conducted in laboratory animals in order to predict and prevent adverse effects of drugs on human reproductive health and development. However, these studies require a relatively large number of animals and are usually conducted late in the drug development process. Early, simple, and inexpensive screening assays could facilitate smarter decisions, reductions in animal use, and development of safe drugs. The current state and future needs for alternative models of developmental and reproductive toxicity are reviewed here. The most popular predictive developmental toxicity assays are embryonic stem cells, rodent whole embryo culture, and zebrafish, each of which involves fairly well-developed techniques with demonstrated utility in drug discovery and development. In vitro or ex vivo methods for male and female reproductive toxicity are less established, but there are promising assays available or being developed that may be useful in drug development, especially for elucidating mechanisms or screening backup compounds. While a number of challenges remain, much progress has been made in alternative developmental and reproductive toxicity models to date, and there is a strong collective enthusiasm in the industry to continue moving them forward. Therefore, it appears that these approaches may be widely used in the near future.
authors.affiliation: Kimberly C. Brannen, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania. Robert E. Chapin, PhD, is a senior research fellow in the Developmental and Reproductive Toxicology Center of Expertise at Pfizer, Inc. in Groton, Connecticut. Abigail C. Jacobs, PhD, is an Associate Director of Pharmacology/Toxicology in the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration in Silver Spring, Maryland. Maia L. Green, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Brannen
authors.affiliation: Kimberly C. Brannen, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania. Robert E. Chapin, PhD, is a senior research fellow in the Developmental and Reproductive Toxicology Center of Expertise at Pfizer, Inc. in Groton, Connecticut. Abigail C. Jacobs, PhD, is an Associate Director of Pharmacology/Toxicology in the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration in Silver Spring, Maryland. Maia L. Green, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Chapin
authors.affiliation: Kimberly C. Brannen, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania. Robert E. Chapin, PhD, is a senior research fellow in the Developmental and Reproductive Toxicology Center of Expertise at Pfizer, Inc. in Groton, Connecticut. Abigail C. Jacobs, PhD, is an Associate Director of Pharmacology/Toxicology in the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration in Silver Spring, Maryland. Maia L. Green, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania.
authors.forename: Abigail C
authors.initials: AC
authors.lastname: Jacobs
authors.affiliation: Kimberly C. Brannen, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania. Robert E. Chapin, PhD, is a senior research fellow in the Developmental and Reproductive Toxicology Center of Expertise at Pfizer, Inc. in Groton, Connecticut. Abigail C. Jacobs, PhD, is an Associate Director of Pharmacology/Toxicology in the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration in Silver Spring, Maryland. Maia L. Green, PhD, is a principal scientist in Safety Assessment and Laboratory Animal Resources at Merck & Co., Inc. in West Point, Pennsylvania.
authors.forename: Maia L
authors.initials: ML
authors.lastname: Green
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D004195:Disease Models, Animal; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions; D053595:Embryonic Stem Cells; D005260:Female; D006801:Humans; D008297:Male; D012098:Reproduction; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests; D015027:Zebrafish
chemical_list: D013723:Teratogens
keywords: alternative; developmental toxicity; embryonic stem cells; ovary; reproductive toxicity; testis; whole embryo culture; zebrafish