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Environmental Factor, April 2015

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NTP hosts regional meeting to highlight juvenile toxicology

By Natasha Catlin and Erin Quist

Darlene Dixon smiling

With contagious enthusiasm, Dixon, one of the meeting organizers, welcomed participants and thanked her co-organizers, Tom Steinbach, D.V.M, with EPL Inc., and Amera Remick, D.V.M, with WIL Research. (Photo courtesy of Steve McCaw)

John Bucher

Bucher gave an overview of NTP, highlighting refinements to traditional assays, including the modified one-generational study, which begins with perinatal dosing and follows all offspring into adulthood, looking at specific endpoints in different groups. (Photo courtesy of Norris Flagler)

David Pedan talking

Peden stressed the need to study early life exposure, saying that we have to study the correct life stage to understand the true effects of exposures. (Photo courtesy of Norris Flagler)

Ikram Elayan talking

Elayan’s regulatory discussion of the FDA views on juvenile toxicity studies generated many questions from participants. (Photo courtesy of Norris Flagler)

Invited speakers from academia, industry, research organizations, and government came to NIEHS March 13 to share their unique perspectives and expertise in juvenile toxicology. Organized by members of the Society of Toxicologic Pathology Education Committee and the Reproductive Pathology Special Interest Group, the regional meeting highlighted toxicology in the morning and pathology challenges in the afternoon.

John Bucher, Ph.D., director of the NIEHS Division of the National Toxicology Program (NTP) opened the meeting with an overview of the program. “There has been a conceptual shift in environmental health sciences from the traditional view of overwhelming the body’s defense by brute force with high doses of chemicals, to [studying] the interactions of chemicals with hormonal systems,” he said.

Bucher pointed out that lower doses influence developmental patterns in more subtle ways. The shift in toxicological studies to look for health effects from perinatal exposures, rather than those in adolescence or adulthood, corresponds with the NIEHS strategic plan goal to study susceptibility across the life span.

Approaches to studying juvenile toxicology

David Peden, M.D., director of the Center for Environmental Medicine, Asthma, and Lung Biology, and head of the Division of Pediatric Allergy, Immunology, and Rheumatology at the University of North Carolina at Chapel Hill, established the importance of the day’s presentations.

“If clinicians are making decisions based on information that’s obtained at the wrong life stage, you may entirely miss major toxicities,” he said, citing the effects of thalidomide. Thalidomide was a sedative, marketed in the late 1950s and early 1960s, that was found to be effective for morning sickness, but unknowingly crossed the placenta causing thousands of birth defects and infant deaths.

Ikram Elayan, Ph.D., with the U.S. Food and Drug Administration (FDA), pointed out that juvenile toxicology studies are needed because traditional studies often fail to obtain data from infancy to adulthood. The choice of endpoints in a juvenile study should be informed by, but not defined by, the adult data, she said.

According to Robert Parker, Ph.D., with Huntingdon Life Sciences, a case-by-case approach to study design is called for. Studies should address all phases of growth and development, he said, as well as both on-target and off-target changes.

LaRonda Morford, Ph.D., with WIL Research, noted that in pediatric drug development studies, pharmacological relevance must be established in the test species.

Pathology perspectives

George Parker, D.V.M., Ph.D., of WIL Research, led off the afternoon session on pathology. Parker discussed challenges, such as postnatal tissue development and the lack of controls animals for those who die unexpectedly. Catherine Picut, V.M.D., J.D., also of WIL Research, reviewed histopathological changes observed in various tissues and organs at early developmental time points.

Toxicology of the developing kidney was addressed by John Seely, D.V.M., from Experimental Pathology Laboratories (EPL) Inc. He pointed out that differences in drug sensitivity are dependent upon the current stage of nephrogenesis, or kidney development, so juvenile nephrotoxicity cannot be estimated from adult data.

Mark Cline, D.V.M., Ph.D., from the Wake Forest School of Medicine, discussed using nonhuman primates, stressing the importance of managing variability, determining whether specific pathogens are present, and documenting objective indicators of age, such as tooth development.

Darlene Dixon, D.V.M., Ph.D., closed the meeting by underscoring the unique factors of juvenile studies. “The importance of studying perinatal and early life effects can’t be overstated,” she said.

(Natasha Catlin, Ph.D., is an Intramural Research and Training Award (IRTA) fellow in the Developmental and Reproductive Toxicology Group, and Erin Quist, D.V.M., is an IRTA fellow in both the NTP Pathology Group and Reproductive Endocrinology Group.)

  • laRhonda Morford speaking

    Morford addressed pharmaceutical studies of small molecules and said that the rat is the preferred species for nonclinical evaluation of pediatric safety. (Photo courtesy of Norris Flagler)

  • George Parker talking

    Discussing the pathology challenges of juvenile toxicity studies, Parker stressed the need for age-matched controls. (Photo courtesy of Steve McCaw)

  • Margarita Gruebbel, Tom Steinbach, and Danielle Brown

    From left, Margarita Gruebbel, D.V.M., Ph.D., EPL Inc.; Tom Steinbach, D.V.M., EPL, Inc.; and Danielle Brown, D.V.M., WIL Research, were among the 70 scientists who gathered for the regional meeting. Steinbach was one of the organizers. (Photo courtesy of Steve McCaw)

  • Catherine Picut talking

    Picut presented a histology atlas of postnatal rat development (Photo courtesy of Steve McCaw)

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