Limitations of Current Toxicity Testing for Identifying Early Life Stage Susceptibilities Gary Ginsberg Connecticut Dept of Public Health NE SRA Regional Chapter June 19, 2007

Introduction Children are not a single receptor group –Broad range of developmental stages and exposure characteristics –Critical windows of development Cancer risk high early post-natal, pubertal Lung development- opportunities for physiologic impairment Immune development – opps for creating allergic phenotype Hormone development – potential impairment of sexual maturation

Intro (continued) Toxicology testing – postnatal not a focus Epidemiology – children not a focus Biomonitoring – very little in children Risk assessment – some focus on children –Assumed captured in 10x inter-human UF –Cancer RA – no inter-human UF –Children’s soil exposure considered but not much else Implications for RA and Public Health???

Standard Toxicology Testing Acute thru chronic testing in young adult rats/mice Cancer bioassays – begin in young adults –Newborn mouse model as faster cancer bioassay ( Fuji, 1991; Flammang, et al., 1997) –Sporadic studies in juvenile rats or mice –Atomic bomb survivors – child risks evaluated –Newborn data analyzed by USEPA and Hattis

Neurotoxicity Testing Adult rats – std part of subchronic testing Developmental neurotox –in utero and postnatal (nursing) exposure –evaluate CNS morphology / behavior in juvenile rats –Trigger – neurotoxic agent eg OPs, pyrethroids, perchlorate, metals Only small percentage of chemicals tested –USEPA Analysis (Makris, 1998) NTT is most sensitive in 2 of 9 pesticides –Limitations: may not involve direct exposure in young Long-term sequelae not evaluated Other types of endpoints not evaluated (immunotox, cancer)

Developmental Studies Prenatal exposure in pregnant females Skeletal and visceral abnormalities No evaluation of post-natal pd Positive findings relevant for newborns? –If yes, then what dose response in newborn? –If equal to prenatal, more restrictive stds What is relevant post-natal exposure pd Negative result – minimal utility for post- natal period

Reproductive Studies Std 2 gen: in utero and post-natal (nursing) exposure Focus is on reproductive success of offspring Limited evaluation of other parameters (e.g. organ wts) Nursing only exposure – what dose received by pups? –Will positive factors in milk mask toxic effects?

Reproductive Studies If positive, implications for sexual maturation, hormonal/endocrine imprinting, If negative, endocrine effects still poss –More subtle maturational/fertility effects Rat fertility may not be most sensitive endpoint –Other endocrine systems may be affected Thyroid, insulin, corticosteroids If positive, typically don’t evaluate windows of vulnerability –Can be key to a risk assessment when pro-rating dose

Toxicity Testing Data Gaps Immunotoxicity in general and especially immuntox in early life –Allergic vs. inflammatory phenotype determined early Respiratory tract development –Juvenile monkey – ozone/asthma model –Airway changes irreversible – narrowed, hyperresponsive –Wouldn’t see it in rodents Primates have much more lung development postnatal than rodents Endocrine – thyroid toxicants – perchlorate Long-term effects of early life exposures

Toxicokinetics for Early Life TK studies not done in juvenile animals TK in children understood from therapeutic drugs PBTK models can simulate internal dose in children Novel pathways/metabolites can exist at immature stages of development Children’s TK not considered in most RA

Unique Exposure Pathways in Early Life Very early ages not well addressed –Breast milk –Reconstituted formula House dust –Pesticides –PFOA –PBDEs –Lead

Biomonitoring in Early Life Lead – all children screened NHANES – Pb, Hg, Cd only Blood bank study – youngest ages have highest blood PFOA Newer methods – diaper analyses

Can RA Do a Good Job on Kids? Children – –highly variable exposure, important TK variability, critical stages of vulnerability Juvenile animals – more sensitive to carcinogens, pesticides Very little epidemiology, biomonitoring Toxicity testing gaps – compounds uncertainty

Implications for RA Standard UFs – may not capture inter-individual and datagaps in child database Logic to FQPA 10x children’s UF Factors to capture greater exposure/minimal chronic pd (2-5x), and greater carcinogen sensitivity (2x) are minimal adjustments Children/juvenile life stages need to receive greater focus in future of tox testing New NAS report on Tox Testing –Concerned with life stages –Major view towards upstream testing, hi thruput, omics