Transcript Toxicity Testing Gaps for Early Life Stages

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
Hattis, et al., EHP 113: 509-516, 2005
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 postnatal 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