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Building a Database of Developmental Neurotoxicants: Evidence from Human and Animal Studies
, S. Padilla1
, T. Shafer1, M. Gilbert1
, J. Breier1,2, J. Cowden1, K. Crofton1
, D. Herr1, K. Jensen1, K. Raffaele3
, N. Radio4, and K. Schumacher5.
1Neurotoxicology Div. U.S. EPA, RTP, NC 27711; 2Curriculum in Toxicology, Univ. of N.C. at Chapel Hill, Chapel Hill, NC, 27514; 3 NCEA/ORD, U.S. EPA,
Washington, DC, 20460; 4Cellumen, Inc., Pittsburgh, PA. 15238; 5U.S. EPA, Region 7, Kansas City, KS, 66101.
Chemicals with Substantial
Evidence: Criteria for Assessment and Endpoints
Developmental Neurotoxicity (n≈100)
EPA’s program for the screening and prioritization of chemicals for
developmental neurotoxicity makes it essential to assemble a list of chemicals
-no in vitro
studies were included.
that are toxic to the developing mammalian nervous system. Listed chemicals will
We included only studies with the pure chemical (or reasonably so).
be used to evaluate the sensitivity, reliability, and predictive power of alternative
developmental neurotoxicity assays. To establish this list, a literature review was
-no human studies were included wherein there was exposure to more than one
conducted for over 400 compounds that have been suggested to be
Aluminum (cl or lactate)
developmental neurotoxicants, neurotoxicants, or developmental toxicants.
We included only studies where the exposure took place during pregnancy or
Compounds were assigned one of three groups based on the strength of the
Epidermal Growth Factor
evidence for developmental neurotoxicity:
We included only studies in which the administered dose was below 5 grams/kg.
(1) no evidence:
either there were no reports that met our criteria for evidence, or
Where knowledge was available, we considered only studies where the
there were reports which showed no developmental neurotoxicity;
administered dose would not be lethal to the offspring.
(2) minimal evidence
: one report only or multiple reports from only one laboratory;
We did not include any case reports.
In studies where the chemical was administered during gestation, to the extent
possible, we looked for a litter-based statistical design.
(3) substantial evidence
: reports from more than one laboratory.
acute pharmacological effects were reported (either during dosing or shortly
The chemicals in the latter group will be especially useful for vetting protocols that
thereafter), we did not include that study.
Butylated Hydroxy Anisol
have been proposed as screens for developmental neurotoxicity.
Endpoints assessed included, but were not limited to
This presentation has been reviewed by the National Health and Environmental Effects Research Laboratory and approved. Approval
does not signify that the contents reflect the views of the Agency.
Methimazole Trypan blue
Chemicals with Minimal
Developmental Neurotoxicity (n≈100)
DNT chemicals (n≈400)
Dichloromethane (methylene chloride)
Amicarbazone (MKH 3586)
Methyl Ethyl Ketone
Dexamethasone is synthetic member of the glucocorticoid class of steroid hormones. It is
used to treat inflammation and autoimmune conditions (e.g
., rheumatoid arthritis), and to counteract side-
BAS 510 (Boscalid)
effects of chemotherapy in cancer patients. Synthetic glucocorticoids, including dexamethasone, are also
administered to women at risk for preterm labor to advance fetal maturation and reduce neonatal
EPTC (S -Ethyl dipropylthiocarbamate)
Phorate (BAS 225 I)
Numerous studies in animals have shown neurodevelopmental effects of perinatal
Brominated veg oil
dexamethasone treatment in rodents. Doses of 0.2 – 3 mg/kg (which encompasses the therapeutic range
in humans) given to the pregnant dam during gestation or to the offspring postnatally alter neurogenesis
and differentiation (Bohn, 1984; Carlos et al., 1992), decrease brain size and brain weight (DeKoskey et
al., 1982; Carlos et al., 1992; Ferguson and Holson, 1999), and alter locomotor activity and learning and
memory behavior (DeKoskey et al., 1982; Vicedomini et al., 1986; Ferguson et al., 2001; Kreider et al.,
2005a). Relatively low doses (0.05 – 0.2 mg/kg) have also been shown to result in long-lasting changes in
neurotransmitter systems and intracellular signaling (Kreider et al., 2005b; Kreider et al., 2006; Slotkin et
Each chemical was assigned to one of three categories:
FK 33-824 (Synthetic enkephalin)
al., 2006). Effects of dexamethasone, including decreased brain weight and hippocampal damage, have
1. No available evidence existed: exclude from
also been observed in nonhuman primates (reviewed in Coe and Lubach, 2005).
Human developmental neurotoxicity is associated with perinatal exposure to
dexamethasone. Prenatal dexamethasone is routinely administered to mothers at risk for preterm delivery
to reduce mortality and the incidence of respiratory distress syndrome and intraventricular hemorage in
2. Minimal evidence existed: put in table in manuscript.
premature infants. Postnatal dexamethasone treatment in preterm infants is also used to reduce the risk
3. Substantial evidence existed: write a descriptive
Triethylene glycol dimethyl ether
and severity of chronic lung disease. A preponderance of epidemiologic and clinical evidence, however,
indicates that both pre- and post-natal exposure to dexamethasone can result in an increased risk for
paragraph for manuscript.
cerebral palsy, decreased brain size, and long-term effects on cognition and behavior (reviewed in Baud,
2004; Purdy, 2004; Purdy and Wiley, 2004; Sloboda et al., 2005).
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