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COMMENTS ON "EFFECT OF PRENATAL EXPOSURE OF DELTAMETHRIN ON THE ONTOGENY OF XENOBIOTIC METABOLIZING CYTOCHROME P450S IN THE BRAIN AND LIVER OF OFFSPRINGS.
Citation:
CROFTON, K. M., J. HARRILL, AND M. WOLANSKY. COMMENTS ON "EFFECT OF PRENATAL EXPOSURE OF DELTAMETHRIN ON THE ONTOGENY OF XENOBIOTIC METABOLIZING CYTOCHROME P450S IN THE BRAIN AND LIVER OF OFFSPRINGS. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 218:96-97, (2007).
Impact/Purpose:
This is a Letter to Editor
Description:
Comments on: Effect of prenatal exposure of deltamethrin on the ontogeny of xenobiotic metabolizing cytochrome P450s in the brain and liver of offsprings [Johri et al. Toxicol Appl Pharmacol. 214:279-289, 2006]
Johri and colleagues recently reported that maternal exposure to deltamethrin, a pyrethroid insecticide, induced transcription of a number of cytochrome P450s in both brain and liver tissue of offspring (Jorhi et al., 2006). Doses reported as ranging from 0.25 to 1.0 mg deltamethrin/kg/day, administered orally to the dam from gestation day 5 to 21 resulted in alterations in the ontogenic profiles of multiple P450s in both tissues. Research on potential developmental effects of pyrethroids is important because of the known exposure to pregnant women of child-bearing age, infants and children (Berkowitz et al., 2003; Heudorf et al., 2004). While the premise of this research is laudable, we must point out that this paper has flaws that prevent any conclusions about the possible effects of deltamethrin on the ontogeny of cytochrome P450s.
The major problem with this paper is the inability to determine the chemical agent, or agents, responsive for the alterations in cytochrome P450s in offspring. The authors conclude multiple times in the paper that deltamethrin caused these effects. For example: ¿The present data indicating alterations in the expression of xenobiotic metabolizing CYPs during development following prenatal exposure to deltamethrin may be of significance as the CYP enzymes are not only involved in the neurobehavioral toxicity of deltamethrin but have a role in regulating the levels of ligands that modulate growth, differentiation, and neuroendocrine functions¿. There is a serious problem with these conclusions: the pregnant dams were not solely exposed to deltamethrin. The authors exposed the pregnant rats to Decis 2.8% EC®, an emulsion that contains 2.8% technical grade deltamethrin and 97.2% unknown 'inerts'. Roussel-Uclaf, the original manufacturer of Decis 2.8% EC®, suggests using the following formulation for an emulsifiable concentrate: 88% xylene, 1% butyl hydroxytoluene, 4% calcium phenylsulfonate, 4% polyglycolic ether of tributylphenol, and 2.8% technical grade (98%) deltamethrin (Fulconis, 1982). While it is unknown exactly what formulation was used in the manufacture the Decis 2.8% EC® used by the authors, the authors' conclusions cannot be attributed solely to deltamethrin exposure. Indeed, some of the 'inerts' may be responsible for the upregulation of P450s reported by the authors. Assuming equivalent ratios of deltamethrin and inerts in all the dose groups, these rats may have been exposed to approximately 8.5, 17, and 34 mg/kg of the inerts (up to 7.5, 15, or 30 mg/kg/day xylene). Exposure during pregnancy to organic solvents is known to induce P450s in both fetal and offspring tissue. Chronic oral maternal exposure to musk xylene at doses of 2-3 mg/kg/day induced hepatic P450s in neonatal rats (Suter-Eichenberger et al., 2000). In addition, inhalation exposure of neonatal rat pups to toluene results in enhanced hepatic EROD activity (Hannson et al., 1985).
The use of commercial mixtures of pesticides in toxicology studies is not at issue here. The problem is that without knowledge of the 'inerts' in the commercial formulation, no conclusions can be made about any one constituent of the commercial mixture. This issue has been raised previously concerning developmental exposures to pyrethroids (Shafer et al., 2005). We beseech both authors and editorial boards to be cognizant of this issue in the future. Concluding that the effects reported in this paper are restricted to deltamethrin exposure is not supported by the data.
These problems in data interpretation should not detract from the fact that Johri et al. (2006) have provided valuable information on the normal ontogeny of P450 mRNAs. These data provide a solid foundation to improve our understanding of the impact of environmental xenobiotics on metabolic processes.
*This document has been reviewed in accordance with the U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
Kevin M. Crofton, Ph.D
Neurotoxicology Division, MD-B105-04
National Health and Environmental Effects
Research Laboratory
US Environmental Protection Agency
Research Triangle Park NC 27711
Joshua A. Harrill
Curriculum in Toxicology
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599
Marcelo J. Wolansky, Ph.D.
National Research Council Fellow
MD-B105-04
US Environmental Protection Agency
Research Triangle Park, NC 27711
References
Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, Landrigan PJ, Wolff MS. (2003) Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort. Environ Health Perspect. 111:79-84.
Fulconis, P. (1982) Chapter 5. Formulation of deltamethrin. In: Deltamethrin Monograph, Paris:Roussel-Uclaf, ISBN 2-904125-01-9, 412 p.
Hansson T, Pettersson BM, Eneroth P, Gustafsson JA. (1985) Neonatal exposure to toluene: effects on the development of liver microsomal cytochrome P-450 and serum hormone levels in the rat. Toxicology. 37:39-50.
Heudorf U, Angerer J, Drexler H. (2004) Current internal exposure to pesticides in children and adolescents in Germany: urinary levels of metabolites of pyrethroid and organophosphorus insecticides. Int Arch Occup Environ Health. 77:67-72.
Johri A, Dhawan A, Lakhan Singh R, Parmar D. (2006) Effect of prenatal exposure of deltamethrin on the ontogeny of xenobiotic metabolizing cytochrome P450s in the brain and liver of offsprings. Toxicol Appl Pharmacol. 214:279-289.
Shafer TJ, Meyer DA, Crofton KM. (2005) Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environ Health Perspect. 113:123-136.
Suter-Eichenberger R, Boelsterli UA, Conscience-Egli M, Lichtensteiger W, Schlumpf M. (2000) CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats. Toxicol Lett.