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PubMed1993

Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits.

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice >> rats >> rabbits.

Animals↗
PubMed1993

Assessment of the developmental toxicity of 2-ethylhexanoic acid in rats and rabbits.

This study was carried out to assess the developmental toxicity of orally administered 2-ethylhexanoic acid (2-EHA) throughout organogenesis in the rat and the rabbit. Treatment of Fischer 344 inbred rats with doses of 100 to 1000 mg 2-EHA/kg/day on (Gestation Days) (GD) 6-15 in a range-finding and a definitive study resulted in a high level of maternal death at 1000 mg/kg/day. Clinical signs of maternal toxicity, including increased liver weight, as well as increased resorptions, dead fetuses, and growth retardation, but no malformations, were observed at 500 mg/kg/day. Slight developmental toxicity, manifested as a reduction in skeletal ossification, occurred in fetuses exposed to 250 mg/kg/day. No adverse effects of treatment were associated with the lower 2-EHA doses (100 and 125 mg/kg/day). Maternal toxicity was also observed in range-finding and definitive studies in New Zealand white rabbits exposed to 25 to 1000 mg 2-EHA/kg/day on GD 6-18 with excessive mortality observed at the highest doses (500 and 1000 mg/kg/day). A low incidence of maternal death as well as abortion occurred following treatment with 125 and 250 mg 2-EHA/kg/day. Less severe clinical signs (reduced weight and food consumption and hypoactivity) were also observed in the 250 mg/kg/day group. There were no adverse effects on fetal viability, growth, or morphology at any dose level. Thus, exposure to 2-EHA during the entire period of organogenesis caused developmental toxicity only at maternally toxic doses in the rat or adverse maternal effects in the absence of developmental toxicity in the rabbit. No evidence of teratogenicity was associated with 2-EHA in this classical safety assessment regimen in either species. The no observed adverse effect levels (NOAELs) for maternal and developmental toxicities in rats are 250 and 100 mg/kg/day, respectively; the corresponding NOAELs for rabbits are 25 mg/kg/day (maternal) and > or = 250 mg/kg/day (developmental).

Abnormalities, Drug-Induced↗
PubMed1997

Maternal and developmental toxicity of polychlorinated diphenyl ethers (PCDEs) in Swiss-Webster mice and Sprague-Dawley rats.

Polychlorinated diphenyl ethers (PCDEs) are industrial byproducts found in many ecosystems at low levels. PCDEs are not markedly toxic to adult rodents, but their developmental toxicity has not previously been examined. We evaluated the maternal and perinatal toxicity of nine PCDE congeners to outbred mice when compounds were administered from gestation day (GD) 6 through GD 15. 2,2',4,4',5,6'-hexaCDE and 2,3',4',6-tetraCDE decreased the number of pups born per female mated and the number of pups surviving per litter born. 2,2',4,4',5,5'-hexaCDE and 2,2',4,5,6'-pentaCDE decreased the number of litters born per female mated, without decreasing postnatal survival. The other PCDEs did not decrease survival either pre- or postnatally. None of the PCDEs caused absence of Harderian glands in surviving offspring at the doses administered. Neither induction of cytochromes P450 nor tissue residues of individual congeners correlated well with developmental toxicity. Three PCDEs were also evaluated in outbred (Sprague-Dawley) rats: 2,2',4,5,6'-pentaCDE and 2,3',4',6-tetraCDE, because of their toxicity to mice; 2,2',4,4',5,5'-hexaCDE, because it should exhibit PCB-like toxicity. Each congener was administered at three dose levels from GD 6 through GD 15. 2,2',4,5,6'-pentaCDE decreased the number of litters born at 100 mg/kg/day, and the survival of pups in litters carried to term, at both 50 and 100 mg/kg per day. Postnatal weight gain was also reduced. In contrast to its action in mice, 2,3',4',6-tetraCDE decreased neither the numbers of litters born nor postnatal survival of rat offspring, but did suppress postnatal weight gain at least through PD 5. As in mice, induction of cytochromes P450 was not well correlated with the developmental toxicity of individual congeners.

Animals↗
PubMed2006

Alternative methods for developmental toxicity testing.

Alternatives to animal testing in developmental toxicology have been the subject of three decades of research. The aims of these investigations have been to reduce animal experimentation, to refine effect assessment and mechanistic studies, and to accelerate and simplify safety testing in an area of toxicology that uses relatively many animals. Many alternatives have been developed over the years with different compexities, using biologic material ranging from continuous cell lines to complete embryos. The validation of alternatives and their application in testing strategies is still in its infancy, although significant steps towards these aims are currently being made. The introduction of the genomics technology is a promising emerging area in developmental toxicity testing in vitro. Future application of alternatives in testing strategies for developmental toxicity may significantly gain from the inclusion of gene expression studies, given the unique programme of gene expression changes in embryonic and foetal development.

Animal Testing Alternatives↗
PubMed2005

Evaluation of the reproductive and developmental toxicity of a fluoroalkylethanol mixture.

The objective of these studies was to evaluate the reproductive and developmental toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluorotelomers. The test substance was administered daily by gavage to Sprague-Dawley rats as a suspension in 0.5% aqueous methylcellulose. In a one-generation reproductive toxicity study, rats (20 per sex per group) were given dosages of 0, 25, 100, or 250 mg kg(-1) day(-1) for a period of 74 days prior to cohabitation, and during mating, gestation, and lactation. Body weights, feed consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance were evaluated for the P1 generation. The F1 offspring were.evaluated during the lactation period for growth and survival and given a gross pathology examination at weaning. A subset of the offspring were retained; body weights, feed consumption, clinical signs, and age at onset of vaginal opening and preputial separation were evaluated, and gross pathology was performed on postnatal day 60. In the developmental toxicity study, groups of time-mated Sprague-Dawley female rats were given the test substance as a suspension in 0.5% aqueous methylcellulose at daily dosages of 0, 50, 200, or 500 mg kg(-1) day(-1) by gavage on gestation days 6-20. During the in-life portion of the study, growth parameters and clinical observations were made. On gestation day 21, dams were euthanized, and the thoracic and abdominal viscera were examined. The uterine contents were removed and examined, and fetuses were evaluated for any alterations. In the reproduction study, litter size at birth, number of live pups per litter on day 0 and 4 of lactation, and pup weights during lactation were reduced in groups administered > or =100 mg kg(-1) day(-1). No other reproductive parameters were affected. There were no adverse reproductive effects observed at 25 mg kg(-1) day(-1). In the developmental toxicity study, reduced maternal body weight parameters, increased perineal fur staining, and increased fetal skeletal alterations were observed at 500 mg kg(-1) day(-1). There was no maternal or developmental toxicity at 50 or 200 mg kg(-1) day(-1). Under the conditions of the studies, the no-observed adverse effect levels for this mixture were 25 mg kg(-1) day(-1) for subchronic toxicity and reproductive parameters and 200 mg kg(-1) day(-1) for developmental toxicity end points. No functional reproductive or developmental effects were observed at dose levels that did not adversely affect adult animals.

Administration, Oral↗
PubMed1999

Developmental toxicity of diethanolamine applied cutaneously to CD rats and New Zealand White rabbits.

Diethanolamine (DEA) was administered cutaneously to pregnant CD rats and New Zealand White rabbits during the periods of major organogenesis, Gestation Days 6-15 for rats and 6-18 for rabbits. Doses employed were 0, 150, 500, and 1500 mg/kg/day for rats and 0, 35, 100, and 350 mg/kg/day for rabbits. Rat dams exhibited reduced body weight at 1500 mg/kg/day, skin irritation and increased kidney weights at 500 and 1500 mg/kg/day, and a slight microcytic anemia with abnormal red blood cell morphology at all dose levels. Rat fetuses had increased incidences of six skeletal variations at 1500 mg/kg/day. Lower doses were without effect on the fetuses. Rabbit dams administered 350 mg/kg/day exhibited various skin lesions, reduced food consumption, and color changes in the kidneys but no hematological changes. Body weight gain was reduced at >/=100 mg/kg/day. There was no evidence of maternal toxicity at 35 mg/kg/day and no evidence of developmental toxicity in rabbits at any dose level. Developmental toxicity was observed only in the rat and only at doses causing significant maternal toxicity, including hematological effects. Due to a dose discrepancy, the no observable effect level (NOEL) for DEA developmental toxicity in rats was adjusted to 380 mg/kg/day. In rabbits, the embryonal/fetal NOEL was 350 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1989

Prediction of risk for human developmental toxicity: how important are animal studies for hazard identification?

To determine how developmental toxicity studies in animals can be used in human risk assessment, a data base was assembled from the literature. It included probable, suspected, unknown, and probably negative teratogenic or embryotoxic drugs and chemical compounds. For each of 175 substances, we recorded the results of any developmental toxicity testing in up to 14 animal species and any reports of mutagenicity or carcinogenicity. Logistic regression and discriminant analysis were used to predict a compound's effect in humans. A measure of the number of positive animal studies and bacterial mutagenicity were important predictors in both models, as were the specific results in hamsters and subhuman primates. The fact that a compound had been tested at all in subhuman primates was more important in predicting human risk than was the result itself. The methods used correctly classified the study compounds 63-91% of the time, depending upon how the suspicious and unknown compounds were treated. The models had a sensitivity of 62-75%, a positive predictive value of 75-100%, and a negative predictive value of 64-91%. These findings imply that studies in laboratory animals carry weight in predicting human developmental toxicity. The more animal species in which a compound is positive, the more likely it is to have a human effect, albeit not the same effect as in the animals. Clinicians should not ignore developmental toxicity tests in animals "because laboratory rats are not like humans."

Abnormalities, Drug-Induced↗
PubMed1990

Analysis of the mechanism of isoniazid-induced developmental toxicity with frog embryo teratogenesis assay: Xenopus (FETAX).

The developmental toxicity of isoniazid (INH) and the metabolites acetylhydrazide (AH) and isonicotinic acid (INA) were examined with the frog embryo teratogenesis assay-Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to INH, AH, and INA for 96 h in two separate static-renewal tests with and without the presence of three differently induced metabolic activation systems (MAS). The MAS consisted of uninduced, Aroclor 1254-induced, and INH-induced rat liver microsomes. Addition of the INH-induced MAS decreased the 96 h LC50 of INH and AH approximately 1.6-fold and 7.9-fold, respectively. The 96 h EC50 (malformation) of INH was virtually unaffected; however, the INH-MAS decreased the teratogenic index (TI) [96 h LC50/96 h EC50 (malformation)] nearly 1.8-fold. The 96 h EC50 (malformation) of AH increased approximately 2.0-fold, decreasing the teratogenic index value 15.8-fold. INA yielded a teratogenic index value of 2.5. Neither the uninduced MAS nor the Aroclor 1254-induced MAS had an effect on any of the compounds tested and none of the MAS affected the developmental toxicity of INA. Results from this study suggest that mixed functional oxidase metabolism may alter the developmental toxicity of INH in vitro by producing a more embryolethal, but less teratogenic metabolite(s) than INH or AH themselves. Results are indicative of the utility and versatility of FETAX in evaluating toxicological mechanisms of teratogenesis in vitro.

Animals↗
PubMed1995

Biological modeling of 5-fluorouracil developmental toxicity.

A biologically-based dose-response (BBDR) model is a mathematical description of the biological events leading to expression of a toxic response. As an alternative to current approaches in non-cancer risk assessment, such models will reduce uncertainty in that they will provide a more comprehensive description of toxicity. We are involved in construction of a BBDR model for the developmental toxicity of 5-fluorouracil (5-FU) in the rat using multiple approaches. First, to identify critical events in the pathogenesis of 5-FU developmental toxicity, thymidylate synthetase (TS) inhibition and alterations in cell kinetics and growth were examined in embryos following maternal administration of 5-FU on day 14 of gestation. A dose-related decline in TS activity was observed within 1 h; however, maximal inhibition and recovery were similar at 10, 20 and 40 mg/kg. Dose-dependent cell cycle alterations were observed within 4 h after exposure and were maximal at 8 h. Hindlimb growth reduction was observed 24 h after exposure to 40 mg/kg, but not at lower doses. At term hindlimb defects were observed at doses above 30 mg/kg. An integrated dose-response model for hindlimb defects was derived from empirical relationships among these events. The resultant dose-response somewhat over-predicted the developmental toxicity of 5-FU, although results of a Monte Carlo simulation indicated that these data were not incompatible with model predictions. Overall, the results suggest that TS inhibition is a key component of the mechanism of 5-FU developmental toxicology, but the model does not capture all of the critical events in the induction of hindlimb defects. A preliminary mechanistic model for the inhibition of embryonic TS, DNA synthesis and cell cycle following maternal exposure to 5-FU, independently derived from literature data to further examine the potential role of this pathway in its developmental toxicity, predicted a dose-response for TS inhibition and DNA synthesis that closely reflected the observed patterns. These results further suggest that TS inhibition, resultant deficits in DNA synthesis and cell cycle perturbations represent a critical mechanistic pathway in the developmental toxicity of 5-FU.

Animals↗
PubMed2006

[Detection of formaldehyde induced developmental toxicity assessed with single cell gel electrophoresis].

To understand the developmental toxicity and the maternal toxicity of formaldehyde (FA), pregnant mice were injected celiac with FA, from the 6th day to the 19th day after the pregnancy. After the birth of fetal mice, the single cell gel electrophoresis (SCGE) was applied to test the DNA damage in liver cells of the maternal mice and of the fetal mice. The experimental results obtained from fetal mice indicate that FA does not induce DNA damage at the low concentration (0.2 mg/kg, P > 0.05), while it could induce DNA breakage at higher concentration as 1.0 mg/kg (P < 0.01). Moreover, DPC(DNA-protein crosslinks) was also initiated at the concentration as 2.0 mg/kg (P > 0.05). When the concentration was up to 20.0 mg/kg, almost all of the DNA is completely joined to form DPC (P > 0.05). The experimental results of pregnant mice indicate that DNA breakage could initiate at relatively low concentration (0.2 mg/kg). Meanwhile, the damage effect was obviously enhanced with the increasing of concentrations (1.0 mg/kg, P < 0.01; 2.0 mg/kg, P < 0.01; 20.0 mg/kg, P < 0.01). No significant increase in DPC formation was observed in pregnant mice, indicating that of all the concentrations of FA tested in the experiment, the DNA damage mainly attributes to DNA breakage. These results suggested that FA has both the maternal toxicity and the developmental toxicity.

Animals↗
PubMed1999

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).

Animals↗
PubMed1990

A critical review of the developmental toxicity and teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: recent advances toward understanding the mechanism.

A specific teratogenic response is elicited in the mouse as a result of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). The characteristic spectrum of structural malformations induced in mice following exposure to TCDD and structurally related congeners is highly reproducible and includes both hydronephrosis and cleft palate. In addition, prenatal exposure to TCDD has been shown to induce thymic hypoplasia. These three abnormalities occur at doses well below those producing maternal or embryo/fetal toxicity and are thus among the most sensitive indicators of dioxin toxicity. In all other laboratory species tested, TCDD causes maternal and embryo/fetal toxicity but does not induce a significant increase in the incidence of structural abnormalities even at toxic dose levels. Developmental toxicity occurs in a similar dose range across species; however, mice are particularly susceptible to development of TCDD-induced terata. Recent experiments using an organ culture were an attempt to address the issue of species and organ differences in sensitivity to TCDD. Human palatal shelves examined in this in vitro system were found to approximate the rat in terms of sensitivity for induction of cleft palate. Investigators have suggested that altered regulation of growth factors and their receptors may involve inappropriate proliferation and differentiation of target cells, ultimately producing TCDD-induced terata. Why the teratogenic effects of TCDD are so highly species and tissue specific, and which animal species most accurately predicts the response of the human embryo/fetus, at the levels of exposure experienced by humans, still remains to be clarified.

Abnormalities, Drug-Induced↗
PubMed1994

Developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the most TCDD-resistant and -susceptible rat strains.

To gain insight into the relationship between TCDD acute toxicity and teratogenicity, developmental effects of TCDD were assessed in the most TCDD-resistant and -sensitive rat strains, Han/Wistar (Kuopio [H/W]; LD50 > 7200 micrograms/kg) and Long-Evans (Turku AB [L-E]; LD50 about 10 micrograms/kg), respectively. A single oral dose of 0, 1, or 10 micrograms/kg TCDD was given to mated female H/W rats on Gestation Day 8 or 12. In L-E rats, the doses were 0, 1, or 5 micrograms/kg TCDD and the exposure took place on Gestation Day 8. Fetuses were examined on Gestational Day 20 for external and soft tissue malformations. TCDD inhibited maternal body weight gain (corrected for weight of uterus with fetuses) at the 10 micrograms/kg dose in H/W rats and at 1 and 5 micrograms/kg in L-E rats. Absolute and relative thymus weights decreased dose-dependently in dams of both strains, but relative liver weights increased only in high-dose H/W dams and low-dose L-E dams. There was a striking interstrain difference in teratogenic outcomes. Over 70% of the live L-E fetuses at 5 micrograms/kg of TCDD exhibited cleft palate, while this effect did not occur in any H/W fetus. Conversely, hydronephrosis and gastrointestinal hemorrhaging appeared dose dependently in live H/W fetuses only. In L-E dams, the incidence of resorptions and late fetal deaths increased up to 75% at 5 micrograms/kg. Edematous dead fetuses and a slightly increased number of resorptions (together 35%) were found in H/W dams at 10 micrograms/kg. Fetal body weights and placental weights decreased at 5 micrograms/kg in L-E rats. In H/W rats, the weights of male placentas decreased at both doses of TCDD. Thus, sensitivity of adult rats to the acute lethal effect of TCDD does not correlate with susceptibility to its developmental toxicity.

Abnormalities, Drug-Induced↗
PubMed2001

[Reproductive and developmental toxicity studies of S-1090, cefmatilen hydrochloride hydrate (2)--A study on oral administration during the period of organogenesis in rats].

Cefmatilen hydrochloride hydrate (S-1090) was administered daily by gavage to female rats at doses of 100, 300 or 1000 mg potency/kg/day from Days 7 to 17 of pregnancy to assess its effects on dams and on development of the embryo-fetuses and offspring. Loose or reddish-brown feces were observed in dams of all the S-1090 dosing groups. Body weight gain was increased from the early stage of administration to the end of pregnancy, food consumption was transiently decreased at the early stage of administration, and water consumption was increased from the middle to the end of pregnancy in all the S-1090 dosing groups. However, no effects on pregnancy, parturition and lactation were observed. Necrospy revealed an increased cecum weight in pregnant and lactating dams of all the S-1090 dosing groups. No effects of S-1090 were observed in viability, growth, incidences of external, skeletal and visceral anomalies, and degree of ossification in F1 fetuses. No effects of S-1090 were observed in such parameters as viability, incidence of external and skeletal anomalies, physical development, sensory functions/reflexes, behavior and reproductive function in F1 offspring. No adverse effects were observed in F2 offspring. On the basis of these results, the no observed adverse effect levels of S-1090 are estimated to be less than 100 mg potency/kg/day for maternal general toxicity, 1000 mg potency/kg/day for maternal reproductive toxicity and the developmental toxicity in the embryo-fetuses and offspring under the conditions of the present study.

Abnormalities, Drug-Induced↗
PubMed2003

Implications of research in male-mediated developmental toxicity to clinical counsellors, regulators, and occupational safety officers.

In closing, let me return to the somewhat irreverent question that I asked at the beginning: Apart from what we learn about fundamentally important biological processes, does male-mediated developmental toxicity make any practical difference? The answer is no, yes, and we don't know. No: The risk of serious birth defects in the future children of a man who is concerned about exposure to radiation or chemicals in the remote past does not appear to be measurably increased in comparison to the background. Yes: Male-mediated developmental toxicity may be of sufficient concern to restrict certain exposures in the population as a whole, but in order for male-mediated developmental toxicity to be determinative, these conditions will have to be otherwise non-toxic. To date, no exposures have been identified that produce substantial male-mediated developmental toxicity in the complete absence of other kinds of toxicity. We don't know how big a problem male-mediated developmental toxicity really is because we have not studied a large enough number and variety of exposures. We don't know if our perspective will change as we begin to understand the importance of individual susceptibility better. We don't know all of the mechanisms that may be involved in male-mediated developmental toxicity or their general biological importance. We don't know more than we do know about male-mediated developmental toxicity, and we are anxious to learn more.

Abnormalities, Radiation-Induced↗
PubMed1987

Evaluation of 60 chemicals in a preliminary developmental toxicity test.

The number of chemicals in commerce which have not been evaluated for potential developmental toxicity is large. Because of the time and expense required by conventional developmental toxicity tests, an abbreviated assay is needed that will preliminarily evaluate otherwise untested chemicals to help prioritize them for conventional testing. A proposed short-term in vivo assay has been used in a series of studies in which a total of 60 chemicals were tested. Some were independently tested two or four times each. In this preliminary test, pregnant mice were dosed during mid-pregnancy and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity. Results in this assay and conventional mouse teratology tests were generally concordant. Conventional data were available for 14 chemicals (ten teratogens, one fetotoxin, three nonteratogens), of which 11 (nine teratogens, one fetotoxin, one nonteratogen) produced evidence of developmental toxicity. This included conventional data for three chemicals (ethylene glycol, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether) that were untested before the present study. As high priority candidates for conventional testing on the basis of results here, all were subsequently studied in a standard teratology assay and were confirmed to be teratogenic in mice. Additionally, one of them (ethylene glycol) plus a fourth high priority candidate for conventional study (diethylene glycol monomethyl ether) were subsequently tested in rats and were found to be teratogenic in that species.

Animals↗
PubMed1988

Developmental toxicity in rats after inhalation exposure of di-2-ethylhexylphthalate (DEHP).

Di-2-ethylhexylphthalate (DEHP) was investigated in Wistar rats for developmental toxicity after head-nose exposure to aerosol concentrations of 0, 0.01, 0.05 and 0.3 mg/l for 6 h per day from gestation day 6 through 15. A range finding study revealed peroxisome proliferation in the liver of the dams throughout exposure levels of 0.2, 0.5 and 1.0 mg/l with an increasing trend. 0.3 mg/l was therefore regarded as an exposure level leading to peroxisome proliferation as a marker for maternal effects. All concentrations were tolerated without clinical signs of maternal toxicity. The fetuses of 20 animals per exposure group were investigated for structural defects. Five additional animals per group were allowed to litter and the offsprings were raised and observed for postnatal signs of toxicity. No significant developmental toxicity or changes in the postnatal physical development were observed. DEHP is assumed not to exhibit developmental toxicity under the experimental conditions employed.

Abnormalities, Drug-Induced↗
PubMed2003

Developmental toxicity of methoprene and several degradation products in Xenopus laevis.

Methoprene is an insect juvenile growth hormone mimic, which inhibits pupation and is used for the control of emergent insect pests such as mosquitoes. Researchers have hypothesized that methoprene use in US may be a contributing factor to the recent increase in malformed amphibians. However, little is known concerning the developmental toxicity of methoprene and its degradation products in amphibians. In these studies, the aqueous stability and developmental toxicity of methoprene and several degradation products (methoprene acid, methoprene epoxide, 7-methoxycitronellal, and 7-methoxycitronellic acid) were examined. Xenopus laevis embryos (stage 8) were exposed to the test chemicals for 96 h. Assays were conducted under static renewal (24 h) conditions and chemical concentrations in water were measured at the beginning and end of the renewal periods. Methoprene exposure did not result in developmental toxicity at concentrations up to 2 mg/l, which is slightly higher than its water solubility. Methoprene acid, a relatively minor degradation product, produced developmental toxicity when concentrations exceeded 1.25 mg/l. Methoprene epoxide and 7-methoxycitronellal caused developmental toxicity at concentrations of 2.5 mg/l and higher. 7-Methoxycitronellic acid was not developmentally toxic at a test concentration as high as 30 mg/l. The five test chemicals had differential stability in aqueous solution that was in some instances affected by the presence of test organisms. These data indicate that methoprene and its degradation products are not potent development toxicants in X. laevis. This, in combination with the fact that field applications of sustained-release formulations of methoprene result in methoprene concentrations that do not typically exceed 0.01 mg/l, suggests that concerns for methoprene-mediated developmental toxicity to amphibians may be unwarranted.

Abnormalities, Drug-Induced↗