Anne-Marie Saillenfait

Pyrethroids: exposure and health effects--an update.

Synthetic pyrethroids are present in numerous commercial insecticide formulations and have extensive indoor and outdoor applications worldwide, including agricultural, public, residential, and veterinary usages for pest control. Pyrethroid use has increased continuously in recent years. The aim of this review is to provide updated and comprehensive information on human exposure and potential hazards associated with this class of pesticides. An initial keyword search in the PubMed database was conducted to identify relevant articles. Were taken into considerations only the studies published in the last decade that have assessed exposure and health effects of pyrethroids in human populations. Literature review shows that exposure evaluations increasingly focus on biomonitoring and that a large number of recent epidemiological studies pertain to the effects of pyrethroids on male fertility and prenatal development. The main metabolites of pyrethroids have frequently been detected in urine samples from the general population, confirming widespread exposure of children and adults to one or more pyrethroids. Non-occupational exposure to pyrethroids mainly occurs through ingestion of residues in food, or ingestion of or dermal contact with contaminated house dust or surface-adhering particles, following domestic use. Although clinical features resulting from acute accidental exposure to pyrethroids are well described (e.g., paraesthesiae, and respiratory, eye and skin irritation), information regarding their chronic effects at low concentrations is both limited and controversial. Several recent epidemiological studies have raised concerns about potentially adverse effects on sperm quality and sperm DNA, reproductive hormones, and pregnancy outcomes. Early neurobehavioural development after in utero exposure is discussed. Further research is needed to clarify the possible risks associated with long-term environmental exposure to pyrethroids.

Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of Di-n-butyl Phthalate Administered to Pregnant Rats

The developmental toxicity and placental transfer of di-n-butyl phthalate (DBP) were evaluated in Sprague-Dawley rats given a single oral dose of DBP on Gestational Day 14. In the developmental toxicity study, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg and were necropsied on GD21. Increased incidence of resorptions and reduced fetal body weight were observed at 1.5 and 2 g/kg. Higher incidences of skeletal variations were found at doses > or = at 1 g/kg. No embryotoxic or teratogenic effects were observed at a dose of 0.5 g/kg. In the placental transfer study, dams were dosed with 0.5 or 1.5 g [14C]DBP/kg. Maternal and embryonic tissues were collected at intervals from 0.5 to 48 h. Embryonic tissues accounted for less than 0.12-0.15% of the administered dose. Levels of radiocarbon in placenta and embryo were one-third or less of those in maternal plasma. No accumulation of radioactivity was observed in the maternal or embryonic tissues. From HPLC analyses, it was shown that unchanged DBP and its metabolites mono-n-butyl phthalate (MBP) and MBP glucuronide were rapidly transferred to the embryonic tissues, where their levels were constantly lower than those in maternal plasma. MBP accounted for most of the radioactivity recovered in maternal plasma, placenta, and embryo. Unchanged DBP was found only in small amounts. These findings support the hypothesis that MBP, a potent teratogen, largely contributes to the embryotoxic effects of DBP.

Developmental toxicity of N-methyl-2-pyrrolidone administered orally to rats

The developmental toxicity of N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NMP at doses of 0 (distilled water), 125, 250, 500, and 750 mg/kg/day, by gavage, on gestational days (GD) 6 through 20. Significant decreases in maternal body weight gain and food consumption during treatment, and a reduction in absolute weight gain were observed at 500 and 750 mg/kg. The incidence of resorptions per litter was significantly higher than control at 500 mg/kg, and rose to 91% at 750 mg/kg. Examination of the foetuses revealed treatment-related malformations, including imperforate anus and absence of tail, anasarca, and malformations of the great vessels and of the cervical arches. The incidence of malformed foetuses per litter, and of litters with malformed foetuses was significantly increased at 500 and 750 mg/kg. At 250 mg/kg, one foetus showed malformations similar to those recorded at higher dosages. There was a dose-related decrease in foetal body weights (male, female, and total) that reached statistical significance at 250 mg/kg. A significant increase in incomplete ossification of skull bones and of sternebrae was also present at 500 and 750 mg/kg. In summary, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 250 and 125 mg/kg/day, respectively. Thus, oral administration of NMP produced developmental toxicity below maternally toxic levels.

Diisobutyl phthalate impairs the androgen-dependent reproductive development of the male rat.

Diisobutyl phthalate (DIBP) is the branched isomer of DBP; DBP side chains have a four-carbon backbone (C4), whereas DIBP has its four-carbon alkyl side chains rearranged into a three-carbon backbone (C3) with a methyl branch. Di-n-butyl phthalate (DBP), and several other ortho-phthalate esters with side-chain lengths of C4-C6, are known to disrupt the androgen-dependent sexual differentiation in the male rat. This study was performed to determine whether in utero exposure to DIBP would induce permanent and dose-responsive alterations of male reproductive development. Pregnant Sprague-Dawley rats were administered olive oil (vehicle control), DIBP or DBP, by gavage on gestation Days 12-21, at doses of 125, 250, 500, 625mgDIBP/(kg day) and 500mgDBP/(kg day). DIBP caused no overt maternal toxicity, nor reduced litter size. Male offspring displayed reduced neonatal anogenital distance (Postnatal day 1, PND) at 250mgDIBP/(kg day) and higher doses, and dose-related retention of areolas/nipples (PND 12-14). Preputial separation (onset of puberty) was delayed in male offspring at 500 and 625mgDIBP/(kg day). Hypospadias, cleft prepuce, and undescended testis were observed in males (11-12 or 16-17 weeks old) exposed in utero to 500 and 625mgDIBP/(kg day). Histopathological lesions were also present in adult testes, mainly consisting in seminiferous tubule degeneration. Our results show that DIBP can cause severe and specific adverse effects on the male rat reproductive development, with a pattern similar to that of DBP. However, DIBP appeared slightly less potent than DBP in inducing malformations.

Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats.

The objective of this study was to evaluate the developmental toxic potential of di‐n‐hexyl phthalate (DnHP) and dicyclohexyl phthalate (DCHP) in rats. Pregnant Sprague–Dawley rats were exposed to DnHP or DCHP at doses of 0 (olive oil), 250, 500 and 750 mg kg–1 per day, by gavage, on gestational days (GD) 6–20. Maternal food consumption and body weight gain were significantly reduced at 750 mg kg–1 per day of DnHP and at the two high doses of DCHP. Slight changes in liver weight associated with peroxisomal enzyme induction were seen in dams treated with DnHP or DCHP. DnHP caused dose‐related developmental toxic effects, including marked embryo mortality at 750 mg kg–1 per day, and presence of malformations (mainly cleft palate, eye defects and axial skeleton abnormalities) and significant decreases in fetal weight at 500 and 750 mg kg–1 per day. Significant delay of ossification and increase in the incidence of skeletal variants (e.g. supernumerary lumbar ribs) also appeared at 250 mg kg–1 per day. DCHP produced fetal growth retardation at 750 mg kg–1 per day, as evidenced by significant reduction of fetal weight. DnHP and DCHP induced a significant and dose‐related decrease in the anogenital distance of male fetuses at all doses, and there was a significant increase in the incidence of male fetuses with undescended testis at 500 and 750 mg kg–1 per day of DnHP. In conclusion, DnHP showed clear embryolethality and teratogenicity, but not DCHP. There was evidence that both phthalates could alter the development of the male reproductive system after in utero exposure, DnHP being much more potent than DCHP. Copyright

Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation exposure

The developmental toxicity of inhaled N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats. Pregnant rats were exposed whole body to NMP vapours at concentrations of 0, 30, 60 and 120 ppm, 6 h/day, on gestational days (GD) 6 through 20. Maternal body weight gain was significantly decreased at 60 and 120 ppm on GD 6-13 and maternal food consumption was reduced at 120 ppm on GD 13-21. No significant difference in the gestational weight change corrected for the weight of the gravid uterus was observed, whatever NMP concentration. There were no adverse effects on embryo/fetal viability or evidence of teratogenicity at any concentration tested. Fetal toxicity indicated by reduced fetal weight was observed at 120 ppm. Thus, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 30 and 60 ppm, respectively.

Developmental toxicities of ethylbenzene, ortho-, meta-, para-xylene and technical xylene in rats following inhalation exposure.

The developmental toxicities of ethylbenzene, o-, m-, p-xylene and technical xylene were studied in Sprague-Dawley rats after inhalation exposure. Animals were exposed to either of these agents at 100, 500, 1000 or 2000 ppm, for 6 h/day, during days 6-20 of gestation. All the agents tested caused maternal toxicity expressed as a reduction in maternal body weight gain at 1000 and 2000 ppm. Decreased corrected weight gain and food consumption were observed at 1000 and 2000 ppm ethylbenzene, o-, m- or p-xylene, and at 2000 ppm technical xylene. No evidence of teratogenic effects was found after exposure to any of these agents up to 2000 ppm. Fetal toxicity evidenced by significant decreases in fetal body weights occurred at concentrations of 500 ppm or greater of o-xylene or technical xylene, and 1000 ppm or greater of ethylbenzene, m- or p-xylene. A significant increase in the mean percentage of fetuses per litter with skeletal variations was also noted at 2000 ppm ethylbenzene, o- and p-xylene. In summary, all tested agents produced developmental toxicity at 1000 and 2000 ppm, concentrations that also produced significant maternal toxicity. With o-xylene and technical xylene, developmental toxicity also occurred at 500 ppm, in the absence of maternal toxic effects. However, the only indication of a treatment-related effect was a slight decrease in fetal weight.

Developmental toxicity of trichloroethylene, tetrachloroethylene and four of their metabolites in rat whole embryo culture

The embryotoxicity of trichloroethylene (TRI) tetrachloroethylene (PER), and of four of their oxidative metabolites i.e. trichloroacetic acid, dichloroacetic acid, chloral hydrate, and trichloroacetyl chloride, was studied in vitro, using the rat whole embryo culture system. Embryos from Sprague-Dawley rats were explanted on gestational day 10 (plug day=day 0) and cultured for 46 h in the presence of the test chemical. All of the tested chemicals produced concentration-dependent decreases in growth and differentiation and increases in the incidence of morphologically abnormal embryos. TRI and PER produced qualitatively similar patterns of abnormalities, while TRI and/or PER metabolites, each elicited clearly distinguishable dysmorphogenic profiles. The presence of hepatic microsomal fractions in the culture medium produced marked decreases in TRI- and PER-induced embryotoxic effects, including mortality, severity of malformations, and delayed growth and differentiation.

Effects of in utero exposure to di-n-hexyl phthalate on the reproductive development of the male rat

Recently, the plasticizer di-n-hexyl phthalate (DnHP) has been demonstrated to be teratogenic and adversely affect the reproductive tract in male rat fetuses. This study was undertaken to determine the long-term effects of an in utero exposure to DnHP on the reproductive development of the male offspring. Di-2-ethylhexyl phthalate (DEHP), another phthalate ester known to disrupt the androgen-dependent sexual differentiation in the male rat, was used as a positive control. Pregnant Sprague-Dawley rats were administered DnHP or DEHP, by gavage on gestation Days 12-21, at doses of 0, 50, 125, 250, or 500 mg DnHP/kg-d and 500 mg DEHP/kg-d. DnHP had no significant effect on maternal body weight gain and pup weights during lactation. The proportion of live pups on postnatal day 1 was slightly, but not significantly, lower than control at 250 and 500 mg DnHP/kg-d. Male offspring displayed reduced anogenital distance on postnatal day 1 (PND) at 125 mg DnHP/kg-d and above, and areola/nipple retention before weaning and at adulthood at 250 and 500 mg DnHP/kg-d. At necropsy on PND 70-78 or PND 111-120, severe malformations of the reproductive tract were observed in young adult males at 125 mg DnHP/kg-d and higher doses. They mainly consisted of hypospadias, underdeveloped testis, and undescended testis. Additionally, histopathological examination revealed seminiferous tubule degeneration at the two high doses. Our results showed that prenatal exposure to DnHP caused permanent and dose-related alterations of the male rat reproductive development, with a similar profile as DEHP.

The effects of maternally inhaled formaldehyde on embryonal and foetal development in rats

Sprague-Dawley rats were exposed to 0, 5, 10, 20 or 40 ppm formaldehyde for 6 hr/day from day 6 to 20 of gestation. On day 21 of gestation the rats were killed for evaluation of maternal reproductive and foetal parameters. No effect on embryonic or foetal lethality, nor significant alterations in the external, visceral or skeletal appearance of the foetuses were noted in any of the exposed groups. Significant concentration-related reduction of foetal body weight occurred at 20 and 40 ppm, and at 40 ppm foetal body weights were 20% less than those of the controls. Maternal toxicity, indicated by significant reduction in body weight and absolute weight gain, was observed at 40 ppm. The results of this study show that formaldehyde is slightly foetotoxic at 20 ppm. Neither embryolethal nor teratogenic effects were observed following inhalation exposure at levels up to 40 ppm.