Developmental and reproductive toxicity studies on artemisone

BACKGROUND: In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed. METHODS AND RESULTS: In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity. CONCLUSIONS: In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed. Birth Defects Res (Part B)86: 131-143, 2009. © 2009 Wiley-Liss, Inc.     

Ethyl t‐butyl ether: review of reproductive and developmental toxicity

Ethyl t‐butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. Knowledge of developmental and reproductive toxicity potential of ETBE is critical for making informed decisions about acceptance and regulations. This review discusses toxicology studies providing information about effects on reproduction and the conceptus. Seven GLP‐compliant studies following widely accepted protocols have focused specifically on developmental and reproductive toxicity (DART) in rats and rabbits exposed to ETBE by gavage with doses up to 1,000 mg/kg body weight/day, the limit specified in standardized test guidelines. Other repeat‐dose general toxicology studies have administered ETBE to rodents for up to 180 days, and included reproductive organ weights, histology, or other indications of reproductive system structure or function. DART potential of the main ETBE metabolite t‐butyl alcohol and class‐related MTBE has also been studied. More GLP‐compliant studies exist for evaluating ETBE using well‐established, currently recommended protocols than are available for many other chemicals used today. The database for determining ETBE DART potential is adequate, although not all study details are currently easily accessible for peer‐review. ETBE does not appear to be selectively toxic to reproduction or embryofetal development in the absence of other manifestations of general toxicity. Studies using recommended methods for sample preservation and analysis have shown no targeted effect on the reproductive system. No embryofetal effects were observed in rabbits. Early postnatal rat pup deaths show no clear dose‐response and have largely been attributed to total litter losses with accompanying evidence of maternal neglect or frank maternal morbidity. Birth Defects Res (Part B) 89:239–263, 2010. © 2010 Wiley‐Liss, Inc.     

The role of maternal toxicity in lovastatin-induced developmental toxicity

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake.     

吸烟对男性生殖和遗传毒性的研究进展

吸烟作为一个社会问题受到广泛关注,目前研究认为吸烟可对生殖系统存在有害影响。从吸烟对睾丸功能、精液质量、生殖内分泌功能的影响及吸烟对生殖细胞的遗传毒作用几个方面,总结了近几年国内外有关吸烟对男性生殖与遗传毒性研究进展,为进一步研究吸烟的生殖毒性提供参考。     

Species‐specificity of ethylene glycol‐induced developmental toxicity: toxicokinetic and whole embryo culture studies in the rabbit

High‐dose gavage exposure to ethylene glycol (EG) is teratogenic in rats, but not rabbits. To investigate the reason for this species difference, toxicokinetic and whole embryo culture (WEC) studies were conducted in gestation day 9 New Zealand White rabbits, and the data compared to very similar data previously generated in pregnant rats. In the toxicokinetic study, maximal levels of unchanged EG in rabbits were comparable to those reported for rats. However, maximal levels of EG's teratogenic metabolite, glycolic acid (GA), in rabbit maternal blood and embryo were only 46% and 10% of the respective levels in rats. The toxicokinetic profile suggested that the lower GA levels in rabbits were due to a slower rate of maternal metabolism of EG to GA, slow uptake of GA into the yolk sac cavity fluid which surrounds the embryo, and negligible transfer via the visceral yolk sac (VYS) placenta. In the WEC study, exposure of rabbit conceptuses to high concentrations (≤12.5 mM) of GA was without effect, which contrasts with reported effects in rat WEC at ≥3 mM. Overall, these data implicate toxicokinetics as an important factor underlying the species difference, although intrinsic insensitivity of the rabbit embryo might also be involved. Integration of these findings with published human data suggest that the rabbit is the more relevant model for human EG exposure, based on the negligible role of the rabbit VYS in placental transfer (humans lack a VYS) and similar rates of EG metabolism and extraembryonic fluid turnover. Birth Defects Res (Part B) 2008. © 2008 Wiley‐Liss, Inc.     

A different approach to validating screening assays for developmental toxicity

BACKGROUND: There continue to be many efforts around the world to develop assays that are shorter than the traditional embryofetal developmental toxicity assay, or use fewer or no mammals, or use less compound, or have all three attributes. Each assay developer needs to test the putative assay against a set of performance standards, which traditionally has involved testing the assays against a list of compounds that are generally recognized as “positive” or “negative” in vivo. However, developmental toxicity is highly conditional, being particularly dependent on magnitude (i.e. dose) and timing of exposure, which makes it difficult to develop lists of compounds neatly assigned as developmental toxicants or not. APPROACH: Here we offer an alternative approach for the evaluation of developmental toxicity assays based on exposures. Exposures are classified as “positive” or “negative” in a system, depending on the compound and the internal concentration. Although this linkage to “internal dose” departs from the recent approaches to validation, it fits well with widely accepted principles of developmental toxicology. CONCLUSIONS: This paper introduces this concept, discusses some of the benefits and drawbacks of such an approach, and lays out the steps we propose to implement it for the evaluation of developmental toxicity assays. Birth Defects Res (Part B) 89:526–530, 2010. © 2010 Wiley‐Liss, Inc.     

Developmental toxicity and uterotrophic studies with di-2-ethylhexyl terephthalate

BACKGROUND: These studies were conducted to evaluate the potential adverse effects of di-2-ethylhexyl terephthalate (DEHT) exposure on in utero development in mice and rats. In addition, a uterotrophic assay for estrogenic activity was conducted in sexually immature rats. METHODS: In the developmental toxicity studies, diet containing DEHT was fed to four groups of mated female Crl:CD(SD)IGS BR rats (25/group) from gestation day (GD) 0-20 or Crl:CD1(ICR) mice (25/group) from GD 0-18. Concentrations within the feed were 0, 0.3, 0.6, and 1.0% for the rats and 0, 0.1, 0.3, and 0.7% for the mice. Laparohysterectomies were carried out on the last day of exposure and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. The fetuses were weighed, sexed, and examined for external, visceral and skeletal malformations, and developmental variations. The dose rate from dietary DEHT exposure was 0, 226, 458, and 747 mg/kg/day in the rats and 197, 592, and 1382 mg/kg/day in the mice for the control, low, mid, and high-exposure groups, respectively. RESULTS: DEHT exposure did not affect clinical observations. A slight reduction in body weight gain was noted in the high-dose level rat group; the remaining groups were unaffected. At necropsy, increased liver weights were noted in the high-dose rat group and the mid- and high-dose mouse groups. Mean numbers of implantation sites and viable fetuses, mean fetal weights, and mean litter proportions of preimplantation loss, early resorptions, late resorptions, and fetal sex ratios were unaffected by DEHT exposures. No test article-related malformations or variations were observed at any concentration level in the rat and mouse developmental toxicity studies. In the uterotrophic assay for estrogenic activity, sexually immature female rats received oral gavage doses 20, 200, or 2000 mg DEHT/kg bw/day from postnatal day (PND) 19-21. A slight reduction in rate of body weight gain was noted on the first day of dosing in the high dose group, but no other indications of toxicity were evident. DEHT exposure did not affect wet or blotted uterine weight parameters in any of these dose groups. The NOEL for developmental toxicity in rats was 747 mg/kg/day and 1382 mg/kg/day in mice. The NOEL for estrogenic activity was 2000 mg/kg/day. The NOEL for maternal toxicity was 458 mg/kg/day in rats and 197 mg/kg/day in mice. CONCLUSIONS: The lack of adverse developmental effects with DEHT exposure are in contrast to the adverse developmental effects noted after di-2-ethylhexyl phthalate (DEHP) exposure. The difference between the effects noted with the ortho-constituent (DEHP) and the lack of effects reported with the para-constituent (DEHT) is due most likely to differences in metabolism and the formation of the stable monoester, mono-2-ethylhexyl phthalate (MEHP) from the DEHP moiety.     

Evaluation of the developmental toxicity of lenalidomide in rabbits

BACKGROUND: Lenalidomide, a thalidomide analog, is indicated for treatment of patients with deletion-5q myelodysplastic syndromes or multiple myeloma. NZW rabbits were used because of sensitivity to thalidomide's teratogenicity. METHODS: Range-finding and pulse-dosing studies preceded a full developmental toxicity study in New Zealand white (NZW) rabbits (25/group) given lenalidomide (0, 3, 10, or 20 mg/kg/day) or thalidomide (180 mg/kg/day) by stomach tube on gestation days (GD) 7-19. Clinical signs, body weights, and feed consumption were recorded daily from GD 7. On GD 29, standard maternal necropsy, uterine content, and fetal evaluations were carried out. RESULTS: In all studies, thalidomide was selectively toxic to development. In the pulse-dosing study, lenalidomide did not affect development at 100 mg/kg/day. Increases in C(max) and AUC(0-24 hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification). Thalidomide selectively reduced fetal body weight, increased postimplantation loss and caused characteristic limb and other dysmorphology. CONCLUSIONS: The maternal and developmental NOAELs for lenalidomide are 3 mg/kg/day. Unlike thalidomide, lenalidomide affected embryo-fetal development only at maternally toxic dosages, confirming that structure-activity relationships may not predict maternal or developmental effects. No fetal malformations were attributable to lenalidomide.     

Spirulina ameliorates arsenic induced reproductive toxicity in male rats

Spirulina (Spirulina platensis), has numerous health benefits including antioxidant, immunomodulatory, and anti-inflammatory activities, works against heavy metal toxicity, and is often used as a food supplement in human, animals, birds and fishes. This study aimed to evaluate the protective ability of the dietary spirulina against the toxic effects of inorganic arsenic (iAs) on male reproductive parameters in rats. Seventy-two mature Long-Evans male rats, dividing into six groups (T0, T1, T2, T3, T4 and T5) (12 rats/group) were included in this study. The T3, T4 and T5 group rats were treated with three consecutive doses (1.0 g, 1.5 g and 2.0 g/kg feed) of spirulina in feed along with 3.0 mg NaAsO₂/kg body weight (BW) in drinking water (DW) daily for 90 days. Each rat of group T1 received NaAsO₂ (3.0 mg/kg BW) in DW, and those of T2 group were fed with spirulina (2.0 g/kg feed) daily for 90 days. The rats of group T0 served as the control with normal feed and water. Total arsenic (tAs) contents, reproductive parameters (testicular weight, sperm motility and morphology), and histological changes in the testicles were evaluated in these rats. Arsenic dosing significantly (p=0.003, Kruskal-Wallis test) increased the tAs contents in the testicles, decreased testes weight, sperm morphology and motility compared to the controls. The effect of arsenic dosing was also evidenced by the histological changes like decreased germinal layers in the seminiferous tubules of the treated rats. Moreover, dietary spirulina (2.0 g/kg feed) supplementation significantly (p=0.011, Kruskal-Wallis test) lowered tAs contents in testicles and increases testes weights, sperm motility and morphology. Therefore, spirulina can be used as an effective dietary supplement to ameliorate the adverse effects of arsenic induced reproductive toxicities. However, further study is required to elucidate the underlying molecular mechanisms of reduction of arsenic induced reproductive toxicity by spirulina.     

Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats

BACKGROUND: Although the potential risk of carbon nanotubes (CNTs) to humans has recently increased due to expanding production and widespread use, the potential adverse effects of CNTs on embryo–fetal development have not yet been determined. METHODS: This study investigated the potential effects of multi‐wall CNTs (MWCNTs) on pregnant dams and embryo–fetal development in rats. MWCNTs were administered to pregnant rats by gavage at 0, 40, 200, and 1,000 mg/kg/day. All dams were subjected to Cesarean section on day 20 of gestation, and the fetuses were examined for any morphological abnormalities. RESULTS: All animals survived to the end of the study. A decrease in thymus weight was observed in the high dose group in a dose‐dependent manner. However, maternal body weight, food consumption, and oxidant–antioxidant balance in the liver were not affected by treatment with MWCNTs. No treatment‐related differences in gestation index, fetal deaths, fetal and placental weights, or sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in incidences of abnormalities between the groups. CONCLUSIONS: The results show that repeated oral doses of MWCNTs during pregnancy induces minimal maternal toxicity and no embryo–fetal toxicity at 1,000 mg/kg/day in rats. The no‐observed‐adverse‐effect level of MWCNTs is considered to be 200 mg/kg/day for dams and 1,000 mg/kg/day for embryo–fetal development. In this study, the dosing formulation was not analyzed to determine the degree of reaggregation (or not), nor were blood levels of CNT's measured in the dosed animals to verify or characterize absorption. Birth Defects Res (Part B) 92:69–76, 2011. © 2011 Wiley‐Liss, Inc.     

Pretreatment with periodate-oxidized adenosine enhances developmental toxicity of inorganic arsenic in mice

BACKGROUND: Inorganic arsenic, given by injection to pregnant laboratory animals, can induce malformations. Arsenic methylation can be inhibited by periodate‐oxidized adenosine (PAD). Severe human health effects from high chronic arsenic exposure have mainly been reported in populations with significant levels of malnutrition, which may enhance toxicity by diminishing arsenic methylating capacity. This study sought to determine the effect of inhibition of arsenic methylation on the developmental toxicity of arsenic in a mammalian model. METHODS: PAD (100 µM/kg, i.p.), was given to pregnant CD‐1 strain mice 30min before 7.5mg/kg sodium arsenite [As(III)], i.p., or 17.9mg/kg sodium arsenate [As(V)], i.p., on gestation day 8 (GD 8; copulation plug=GD 0). Control dams received As(III), As(V), or PAD alone or were untreated. Test dams were killed on GD 17, and their litters were examined for mortality and gross and skeletal defects. RESULTS: Pretreatment with PAD before either arsenical resulted in increased maternal toxicity and lower fetal weights. Pretreatment also caused higher prenatal mortality, with 8 of 21 and 5 of 17 litters totally resorbed in the PAD plus As(III) and PAD plus As(V) treatment groups, respectively. Significant increases in the incidences of exencephaly, ablepharia, and anomalies of the vertebral centra, sternebrae, and ribs were also associated with PAD pretreatment. Short tail (3 fetuses in 3 litters) was seen only following PAD plus As(III) treatment. CONCLUSIONS: These results demonstrate that the developmental toxicity of inorganic arsenic can be enhanced by PAD, due possibly to inhibited methylation of arsenic. Birth Defects Res B 68:335–343, 2003. © 2003 Wiley‐Liss, Inc.     

Understanding dioxin developmental toxicity using the zebrafish model

Zebrafish (Danio rerio) have advantages over mammals as an animal model for investigating developmental toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a persistent global contaminant, is the most comprehensively studied developmental toxicant in zebrafish. The hallmark responses of TCDD developmental toxicity manifested in zebrafish larvae include edema, anemia, hemorrhage, and ischemia associated with arrested growth and development. Heart and vasculature development and function are severely impaired, and jaw malformations occur secondary to inhibited chondrogenesis. The swim bladder fails to inflate, and the switch from embryonic to adult erythropoiesis is blocked. This profile of developmental toxicity responses, commonly referred to as "blue sac syndrome" because the edematous yolk sac appears blue, is observed in the larval form of all freshwater fish species exposed to TCDD at the embryonic stage of development. Components of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AHR/ARNT) signaling pathway in zebrafish have been identified and functionally characterized. Their role in mediating TCDD toxicity has been determined using morpholinos to specifically knockdown the translation of zfAHR1, zfAHR2, zfARNT1, and zfARNT2 mRNAs, respectively, and a line of zfARNT2 null mutant zebrafish has provided further insight. These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity. In addition, the growing use of molecular and genomic tools for research on zebrafish have led to advances in our understanding of the mechanism of TCDD developmental toxicity at the molecular level, including the recent finding that toxicity is not mediated by increased cytochrome P4501A (zfCYP1A) expression.     

Evolutionary innovations of squamate reproductive and developmental biology in the family Chamaeleonidae

The availability of molecular phylogenies has greatly accelerated our understanding of evolutionary innovations in the context of their origin and rate of evolution. Here, we assess the evolution of reproductive mode, developmental rate and body size in a group of squamate reptiles: the chameleons. Oviparity is ancestral and viviparity has evolved at least twice: Bradypodion and members of the Trioceros bitaeniatus clade are viviparous. Viviparous species are medium‐sized as a result of convergence from either small‐sized ancestors or large‐sized ancestors, respectively, but do not differ from oviparous species in clutch size, hatchling size or the trade‐off between clutch and hatchling size. Basal chameleons (Brookesia, Rhampholeon and Rieppeleon) are small‐sized and have developmental rates comparable with those of other lizards. Derived chameleons (Calumma, Chamaeleo, Trioceros and Furcifer) are mostly large‐sized and all have relatively slow developmental rates. Several clades of derived chameleons also exhibit developmental arrest (embryonic diapause or embryonic diapause plus cold torpor) and incubation periods extend to 6–10 months or more. Developmental arrest is associated with dry, highly seasonal climates in which the period favourable for oviposition and hatching is short. Long incubation periods thus ensure that hatching occurs during the favourable season following egg laying. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 100 , 656–668.     

Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development

BACKGROUND: A review of the nonsteroidal anti‐inflammatory drug (NSAID) literature suggested occurrences of low‐level incidences of cardiovascular and midline defects in rabbit fetuses exposed in utero. Aspirin (acetylsalicylic acid, ASA) is a widely used NSAID that irreversibly inhibits cyclooxygenases (COXs) 1 and 2. ASA has been studied extensively in rats and has consistently increased low‐incidence cardiovascular malformations and defects in midline closure. The objectives of the current study were to comprehensively define the developmental toxicology profile of ASA in rabbits by using a dosing paradigm encompassing the period of organogenesis and to test the hypothesis that maternal gastrointestinal toxicity after repeated dose administrations hampers the detection of low‐incidence malformations with ASA in rabbits by limiting ASA administration to sensitive windows for cardiovascular development and midline closure. METHODS: ASA was administered to pregnant New Zealand White rabbits from gestation days (GDs) 7 to 19 at dose levels of 125, 250, and 350 mg/kg per day and as single doses of 500, 750, or 1000 mg/kg on GD 9, 10, or 11. Cesarean sections were performed on GD 29, and the fetuses were examined for external, visceral, and skeletal development. RESULTS: In the repeated dose study, maternal toxicity was exhibited in the 250‐ and 350‐mg/kg per day groups by mortality and decreased food consumption and body weight gain. In the single dose studies, maternal toxicity was exhibited at all doses by reductions in body weight gain and food consumption for 3 days after treatment. Fetal body weight was significantly reduced in the repeated dose study at 350 mg/kg per day. Fetal weights were not affected by single doses of ASA on GD 9, 10, or 11. There were no treatment‐related external, visceral, or skeletal malformations associated with ASA administration throughout organogenesis or with single doses administered during critical developmental windows. CONCLUSION: These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development. Birth Defects Research (Part B) 68:38–46, 2003. © 2003 Wiley‐Liss, Inc.     

Reduced water intake: Implications for rodent developmental and reproductive toxicity studies

In developmental and reproductive toxicity studies, drinking water is a common means of delivering the test agent. Reduced consumption of toxicant-containing water raises questions about indirect effects of reduced maternal fluid consumption resulting from unpalatability, versus direct effects of the test compound. Issues to consider include: objective assessment of dehydration and thirst, the relative contributions of innate and learned behaviors to drinking behavior and flavor preference, and the objective assessment of physiologic stress. Not only do lab animals under ad lib conditions consume more water than the minimum required to maintain fluid balance, animals faced with water restriction have substantial physiologic capacity for protection of metabolic processes. Measures of blood biochemistry can provide quantifiable, objective indications of fluid balance, but changes in these parameters could result from other causes such as effects of a test toxicant. Consummatory behaviors in response to perceived need are highly influenced by learning. Hence, the drinking behavior, water intake, and flavor acceptance/preference of animals used in toxicology experiments could be subject to learning experiences with the test compound. Physiological symptoms of stress produced by water deprivation may be distinguishable from the symptoms associated with other generalized stressors, such as food deprivation, but doing so may be beyond the scope of most developmental or reproductive toxicity studies. Use of concurrent controls, paired to test groups for water consumption, could help distinguish between the direct effects of a test toxicant as opposed to effects of reduced water consumption alone. Birth Defects Res (Part B), 86:157–175, 2009. ©2009 Wiley-Liss, Inc.     

Challenges in constructing statistically based structure-activity relationship models for developmental toxicity

Regulatory agencies are increasingly called upon to review large numbers of environmental contaminants that have not been characterized for their potential to pose a health risk. Additionally, there is special interest in protecting potentially sensitive subpopulations and identifying developmental toxicants that may be present in the environment. Thus, there is an urgent need for efficient methods to screen large numbers of chemicals for their potential to pose a developmental hazard. One potential screening method involves the use of statistically based structure-activity relationship (SAR) tools to predict activity of untested chemicals. Such systems rely on statistical analyses to discern relationships between structure and activity for a training set of substances. Predictions can then be made for an untested substance as long as its structural features are encompassed by chemicals of the training set. In theory, such systems could assist regulatory agencies in their screening efforts; however, to date, there has been little independent evaluation of these tools for this use. To contribute to such an evaluation, the International Life Sciences Institute Risk Science Institute (ILSI RSI) convened a Working Group to examine methodology used to construct statistically based SAR systems for developmental toxicity. This document reports on the deliberations of the Working Group, which concluded that an improved process is needed for utilizing developmental toxicity data in the construction of statistically based SAR models. The process must be objective, reproducible, rational and transparent. Moreover, it must be informed by the expertise of developmental toxicologists and biologists and must be subject to peer review.     

Effects of protein deficient diets on the developmental toxicity of inorganic arsenic in mice

BACKGROUND: Inorganic arsenic, when given by injection to pregnant laboratory animals (mice, rats, hamsters), has been shown to induce malformations. Arsenic methylation may be a detoxification step, and diets deficient in protein are a poor source of methyl donors and may possibly result in impaired arsenic methylation. Human health effects from chronic arsenic exposure have been reported mainly in populations with low socioeconomic status. Individuals in such populations are likely to suffer from malnutrition, which can compromise embryonic/fetal development and diminish arsenic methylating capacity. We sought to determine if dietary protein deficiency affects the developmental toxicity of inorganic arsenic. METHODS: Mated females were randomly assigned to one of 12 treatment groups. Experimental groups received either AsIII or AsV i.p. on Gestation Day 8 (GD 8, plug=GD 0) and were maintained on a 5%, 10%, or 20% protein custom mixed diet from GD 1 until sacrifice. Controls received the custom diets alone, were given AsIII or AsV i.p. on GD 8 with Teklad LM-485 rodent diet, or were fed the LM-485 diet alone. Test females were sacrificed on GD 17, and their litters were examined for mortality and developmental defects. RESULTS: Arsenic plus dietary protein deficiency decreased maternal weight gain and increased the incidences of exencephaly, ablepharia, and skeletal defects, such as malformed vertebral centra, fused ribs, and abnormal sternebrae (bipartite, rudimentary, or unossified). CONCLUSIONS: These results demonstrate that dietary protein deficiency enhances the developmental toxicity of inorganic arsenic, possibly by impairment of arsenic methylation.     

毒死蜱对神经系统发育毒性作用的研究进展

毒死蜱是目前广泛使用的一种有机磷农药,它对人体及其它生物体的毒性作用越来越受到广泛关注。就其理化性质和神经系统发育毒性作用进行综述。     

杀扑磷抗性获得对奥氏钝绥螨发育历期与繁殖能力的影响

为探索杀扑磷抗性获得对奥氏钝绥螨Amblyseius womersleyi Schicha发育历期与繁殖能力的影响,研究了在25℃与30℃温度下,奥氏钝绥螨的杀扑磷抗性系与敏感系的发育历期与繁殖能力。结果表明：奥氏钝绥螨的杀扑磷抗性系与敏感系的交配产卵行为习性没有差异。在25℃与30℃温度下,奥氏钝绥螨的各发育历期、产卵期、产卵高峰期,每雌日产卵量与总产卵量,卵孵化率及雌雄成螨性比等,在杀扑磷抗性系与敏感性系之间无明显差异。结果说明杀扑磷抗性获得对奥氏钝绥螨的发育历期与繁殖能力没有明显影响。