Penetration and migration success of Diplostomum spp. cercariae in Arctic charr.

We exposed 2 groups of young-of-the-year Arctic charr (Salvelinus alpinus) singly to 54 +/- 2 (mean +/- SE) Diplostomum spp. cercariae that had emerged from 4 randomly sampled snail hosts (Lymnaea stagnalis). The rearing tanks of the fish received Diplostomum spp. cercariae via the incoming water; therefore, 18 of the 36 fish had parasites in their eyes before the experimental exposure. Of the Diplostomum spp. cercariae presented to the fish, 19% penetrated and 46% of those that had penetrated the fish migrated successfully to the lens of the fish eye. The migration success of Diplostomum spp. from the site of penetration to the fish eye lens was lower in the previously parasitized (37.0 +/- 8.7% [mean +/- SE] adjusted with the number of penetrated cercariae) than in the unparasitized fish (55.3 +/- 8.8%) and differed between the individual snail host from which the cercariae had emerged. In addition, the migration success of Diplostomum spp. decreased with an increase in the number of the cercariae that penetrated the fish. At the individual snail host level, there seemed to be a trade-off between penetration and migration ability of the cercariae. The results indicate that success of Diplostomum spp. in penetration and especially in migration to the fish eye is affected by both the molluscan first intermediate host and the piscine second intermediate host.

Metabolic depression and spleen and liver enlargement in juvenile Arctic charr Salvelinus alpinus exposed to chronic parasite infection.

The present study on the connection between standard metabolic rate (R(S)) and chronic Diplostomum spp. infection resulted in a decrease in R(S), and an enlargement in spleen and liver sizes in the infected juvenile Arctic charr Salvelinus alpinus compared to control fish. As splenic enlargement observed in infected fish was not due to condition-related changes in the spleen, it could most probably be explained by increased leucocyte synthesis. The higher liver masses in infected S. alpinus may have been related to disorders in energetic function, which could have had major effects on biochemical regulation by the liver. The proposed metabolic syndrome with a possible reduction in insulin sensitivity in tissues results in ineffective glucose and lipid metabolism and thus it is suggested that chronic Diplostomum infection in S. alpinus might not impose direct energetic costs, but it may weaken the efficiency of energy metabolism and thus lead to lowered R(S).

Metabolic rate, growth and aggressiveness in three Atlantic salmon Salmo salar populations.

Standard metabolic rate (R(S)), specific growth rate (G) and aggressiveness were investigated in three Finnish populations of Atlantic salmon Salmo salar (Neva, Saimaa and Teno), which were reared in identical hatchery conditions. The populations differed in their geographical origin and native habitat. There was a significant difference between populations in R(S): the southernmost Neva population had higher values in R(S) than the northernmost Teno population. No difference was found in G or aggressiveness between the populations. G was found to have a significant positive association with aggressiveness and R(S) among the three populations, however, these results were not statistically significant after correction for multiple tests. There was no significant association between R(S) and aggressiveness. Higher metabolic rate of the most southern population Neva is suggested to be an adaptation to the more abundant food sources of the southern stream.

Effects of mobile phone radiation on UV-induced skin tumourigenesis in ornithine decarboxylase transgenic and non-transgenic mice.

PURPOSE: The effects of low-level radiofrequency radiation (RFR) on ultraviolet (UV)-induced skin tumorigenesis were evaluated in ornithine decarboxylase (ODC) and non-transgenic mice. MATERIALS AND METHODS: Transgenic female mice over-expressing the human ODC gene and their non-transgenic littermates (20 animals in the cage control group, and 45-49 animals in the other groups) were exposed for 52 weeks to UV radiation or a combination of UV radiation and pulsed RFR. The UV dose was 240 Jm(-2) (1.2 x human minimum erythemal dose) delivered three times a week. One group of animals was exposed to Digital Advanced Mobile Phone System (DAMPS)-type RFR, the other group to Global System for Mobile (GSM)-type RFR at a nominal average specific absorption rate of 0.5 W kg(-1), 1.5 h day(-1), for 5 days a week. The skin was carefully palpated weekly for macroscopic tumours. Histopathological analyses of all skin lesions and of a specified dorsal skin area were performed on all animals. RESULTS: UV exposure resulted in development of macroscopic skin tumours in 11.5 and 36.8% of non-transgenic and transgenic animals, respectively. The RFR exposures did not give a statistically significant effect on the development of skin tumours in either transgenic or non-transgenic animals, or in combined analysis, but tumour development appeared slightly accelerated especially in non-transgenic animals. No effects of RFR exposures were found on excretion of 6-hydroxymelatonin sulphate into urine or on polyamine levels in dorsal skin. CONCLUSION: RFR exposures did not significantly enhance skin tumourigenesis. However, the slightly accelerated tumour development may warrant further evaluation.

Effects of mobile phone radiation on X-ray-induced tumorigenesis in mice.

The increased use of mobile phones has raised the question of possible health effects of such devices, particularly the risk of cancer. It seems unlikely that the low-level radiofrequency (RF) radiation emitted by them would damage DNA directly, but its ability to act as a tumor promoter is less well characterized. In the current study, we evaluated the effect of low-level RF radiation on the development of cancer initiated in mice by ionizing radiation. Two hundred female CBA/S mice were randomized into four equal groups at the age of 3 to 5 weeks. The mice in all groups except the cage-control group were exposed to ionizing radiation at the beginning of the study and then to RF radiation for 1.5 h per day, 5 days a week for 78 weeks. One group was exposed to continuous NMT (Nordic Mobile Telephones)-type frequency-modulated RF radiation at a frequency of 902.5 MHz and a nominal average specific absorption rate (SAR) of 1.5 W/kg. Another group was exposed to pulsed GSM (Global System for Mobile)-type RF radiation (carrier-wave frequency 902.4 MHz, pulse frequency 217 Hz) at a nominal average SAR of 0.35 W/kg. The control animals were sham-exposed. Body weight, clinical signs, and food and water consumption were recorded regularly. Hematological examinations and histopathological analyses of all lesions and major tissues were performed on all animals. The RF-radiation exposures did not increase the incidence of any neoplastic lesion significantly. We conclude that the results do not provide evidence for cancer promotion by RF radiation emitted by mobile phones.

Development of preimplantation mouse embryos after exposure to a 50 Hz magnetic field in vitro.

Effect of sinusoidal 50 Hz magnetic field (MF) on development of preimplantation CBA/S mouse embryos in vitro was studied. Superovulated and in vivo fertilized preimplantation embryos were collected at one cell stage and divided to control and MF-exposed groups. Sinusoidal 50 Hz MF with field strength of 10 A/m r.m.s., corresponding a flux density of 13 microT r.m.s., was used to expose the embryos in culture at 37 degrees C in a CO2-incubator. The developmental stage and abnormalities were recorded twice daily except once daily during weekends. The vitality and developmental stages of the embryos were similar in both groups although slightly more dead embryos were found during the 1st day in MF-exposed group (P<0.05) and the development of MF-exposed embryos was slightly impaired. In conclusion, the exposure to sinusoidal 50 Hz MF at field strength of 10 A/m did not significantly disturb the development of the mouse embryos in vitro up to the blastocyst stage.

Prenatal testosterone and luteinizing hormone levels in male rats exposed during pregnancy to 2,3,7,8-tetrachlorodibenzo-p-dioxin and diethylstilbestrol.

Changes in the perinatal testosterone surge have been related to demasculinization of the central nervous system and androgen-dependent growth of the reproductive organs in male mammals. Earlier reports suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interferes with androgen production, but the perinatal effects have remained elusive. In the present study we explored in utero-effects of TCDD (0.05, 0.1, 0.5, and 1.0 microg/kg), introduced on day 13.5 of pregnancy, on prenatal (day 19.5 post-conception [p.c.]) testosterone (T) surge and pituitary luteinizing hormone (LH) production in TCDD-resistant Han/Wistar (H/W) and TCDD-sensitive Long-Evans (L-E) rats. To elucidate estrogenic effects on T and LH production, Sprague-Dawley (S-D) fetuses with previously known DES-sensitivity were exposed in utero to diethylstilbestrol (DES, 100-300 microg/kg) on days 13.5, 15.5, and 17.5 p.c. For comparison, H/W fetuses that responded to TCDD treatments were exposed to DES at concentration of 100 microg/kg. It was found that TCDD has a stimulatory effect on testicular T synthesis in the H/W fetuses and that their circulating T concentrations increased significantly. The effect was not seen in the inbred L-E fetuses, which throughout the study showed considerably low testicular T levels. Pituitary LH concentrations also increased in the H/W fetuses exposed to TCDD. Effects of TCDD (1.0 microg/kg) in the H/W fetuses could be confirmed in vitro by human chorionic gonadotropin (hCG) stimulation assay showing the highest response rate in the TCDD exposed testes. Stimulation of cyclic AMP (adenosine-3', 5'-cyclic monophosphate[cAMP]) production was not considerably altered by in utero TCDD exposure. A significant depression in testicular and plasma T content was seen in the DES-exposed S-D and H/W fetuses, but pituitary LH levels did not alter considerably. In the presence of hCG, DES-exposed testes showed lower in vitro T and cAMP production rates compared to the untreated testes. TCDD (1.0 microg/kg) increased and DES decreased the male body weight gain, but the changes were not sex-dependent. It is concluded that TCDD may increase the amplitude of the prenatal testosterone surge in male rats by stimulating pituitary LH production and enhancing the sensitivity of the fetal testis to LH. DES, on the contrary, apparently impairs testicular steroidogenesis and pituitary function.

Effects of 50 Hz magnetic fields on cancer induced by ionizing radiation in mice.

PURPOSE: To evaluate the effects of 50 Hz magnetic fields (MF) on the development of cancer induced by ionizing radiation. MATERIALS AND METHODS: A total of 150 female CBA/S mice were randomized into three equal groups at the age of 3-5 weeks. One of the groups served as a 'cage-control group'. The two other groups were exposed to ionizing radiation in the beginning of the study. One of these two groups was exposed 24 h per day, for 1.5 years, to a 50Hz vertical MF, the intensity of which varied regularly between 1.3, 13 and 130 muT. The other served as a control group and was sham-exposed to MF in similar, but unenergized, exposure racks. Body weights, clinical signs, and food and water consumption were recorded regularly. Haematological examination, and the histopathological analysis of all lesions and major tissues were performed on all animals. RESULTS: MF exposure did not increase the incidence of any primary neoplasms. However, the incidence of basophilic liver foci, a probable pre-neoplastic change in liver, was increased. The incidence of hepatocellular adenomas was unchanged, whereas the incidence of hepatocellular carcinomas was slightly, but not statistically significantly, elevated. CONCLUSIONS: It is concluded that overall the results of this study do not support a role for MF as a tumour promoter.

Effects of low-frequency magnetic fields on implantation in rats.

Effects of 50-Hz sinusoidal magnetic fields (MFs) on embryo implantation, serum 17beta-estradiol, progesterone, testosterone, and melatonin levels, and on estrogen receptor (ER) and progesterone receptor (PgR) densities in the uterus were studied during the preimplantation and implantation periods in rats. Pregnant Wistar rats were exposed to magnetic r.m.s. field strengths of 10 or 100 A/m (13 or 130 microT) or sham-exposed (controls) from day 0 of pregnancy for 24 h/day and killed during light and dark periods between 70 h and 176 h after ovulation. MFs did not influence the mean total number of implantations. The nocturnal mean serum melatonin concentration decreased by 34 and 38% at 10 and 100 A/m, respectively. At the same time, the first embryos, at an early developmental stage, arrived in the uterus in the MF-exposed groups. Serum estradiol and progesterone levels did not significantly change. Nuclear PgR and ER densities in the uterus decreased before implantation and there was an increased incidence of early stage embryos and fewer hatched embryos were found in the uterus at 100 A/m. During the early implantation period, the uterine cytosolic ER/PgR-ratio was increased at 100 A/m and no implants were concomitantly found in uterus. The nuclear ER/PgR-ratio decreased during implantation in both MF-groups due to decreased nuclear ER density. At the same time, 19% and 15% of the embryos (calculated from the corpora luteae) at 10 and 100 A/m, respectively, were yet morulae and not implanted. In summary, the results show that MFs do not impair implantation in rats although there may be some borderline changes in the transport and development of embryos and associated endocrinologic parameters.

3-Cloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a rat thyroid gland carcinogen, does not affect serum levels of TSH and thyroid hormones.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a chlorine disinfection by-product in drinking water, causes follicular adenomas and carcinomas in thyroid glands of Wistar rats with an unknown mechanism. We evaluated effects of MX on blood thyroid stimulating hormone (TSH), thyroxine (T(4)), triiodothyronine (T(3)), prolactin (PRL) and growth hormone (GH) levels in male and female Wistar rats to assess their role in the tumorigenesis. The levels of TSH, PRL and GH in serum of male rats were not significantly affected by a single dose of 1, 10 or 60 mg/kg of MX administered by gavage 2 h before sampling. In repeated dose experiments MX was administered at dose levels of 1, 10 or 60 mg/kg of MX (40 mg/kg for females) in water by gavage daily for 1 or 3 weeks. Thyroid glands, adrenal glands and the liver were evaluated for morphological changes and cell proliferation activity after staining with proliferating cell nuclear antigen (PCNA). The dose of 60 mg/kg MX was toxic upon repeated administration. Nevertheless, MX did not affect blood TSH and T(4) levels at any time point in either sex. T(3) concentration increased transiently in males (by 37% after week 1) at the highest MX dose but not in females. MX did not change the weights of thyroid glands, their morphology and cell proliferation activity by the end of the week 3. MX did not affect blood PRL levels but decreased GH levels in males at all doses after the first week of MX treatment. The results indicate that MX does not alter blood TSH and thyroid hormone levels in rats, and imply that MX may not cause thyroid follicular cell tumors by TSH-mediated hormonal promotion.

Development of prediction models for three in vitro embryotoxicity tests in an ECVAM validation study.

Since 1997 the National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments, ZEBET, in Berlin, has been coordinating a validation study aimed at prevalidation and validation of three in vitro embryotoxicity tests, funded by the European Center for the Validation of Alternative Methods (ECVAM) at the Joint Research Center (JRC, Ispra, Italy). The tests use the cultivation of postimplantation rat whole embryos (WEC test), cultures of primary limb bud cells of rat embryos (micromass or, MM, test), and cultures of a pluripotent mouse embryonic stem cell line (embryonic stem cell test or EST). Each of the tests was performed in four laboratories under blind conditions. In the preliminary phase of the validation study 6 out of 20 test chemicals comprising different embryotoxic potential (non, weakly, and strongly embryotoxic) were tested. The results were used to define biostatistically based prediction models (PMs) to identify the embryotoxic potential of test chemicals for the WEC test and the MM test. The PMs developed with the results of the preliminary phase of the validation study (training set) will be evaluated with the results of the remaining 14 test chemicals (definitive phase) by the end of the study. In addition, the existing, improved PM (iPM) for the EST, which had been defined previously, was evaluated using the results of the preliminary phase of this study. Applying the iPM of the EST to the results of this study, in 79% of the experiments, chemicals were classified correctly according to the embryotoxic potential defined by in vivo testing. For the MM and the WEC test, the PMs developed during the preliminary phase of this validation study provided 81% (MM test) and 72% (WEC test) correct classifications. Because the PM of the WEC test took into account only parameters of growth and development, but not cytotoxicity data, a second PM (PM2) was developed for the WEC test by incorporating cytotoxicity data of the differentiated mouse fibroblast cell line 3T3, which was derived from the EST. This approach, which has previously never been used, resulted in an increase to 84% correct classifications in the WEC test.

Site dependent bioavailability and metabolism of levosimendan in dogs.

Site specific bioavailability and metabolism of levosimendan was studied in ten dogs by placing intestinal access port catheters in different parts of the gastrointestinal tract. 14C-labelled levosimendan (0.1 mg/kg) was administered intravenously, by gastric tube and directly through catheters that were placed in the duodenum, jejunum and ileum. Plasma samples were collected and radioactivity in the different organs and tissues was measured. The results of the present study showed that bioavailability of levosimendan was high varying from 71 to 86% after extravascular administration. Metabolite OR-1855 concentrations in the plasma were about 3-4 times higher after administration to the ileum compared to the other administration routes. It can be concluded that the bioavailability of levosimendan is not affected by site specific administration. The bacteria or enzymes responsible for the metabolism of levosimendan are located in the lower parts of the gastrointestinal tract.

[Development of prediction models for three in vitro embryotoxicity tests which are evaluated in an ECVAM validation study] / Die Entwicklung von Prädiktionsmodellen für drei in vitro Embryotoxizitätstests im Rahmen einer ECVAM Validierungsstudie.

In 1997 ZEBET started the co-ordination of a study funded by the European Centre for the Validation of Alternative Methods (ECVAM) with the aim of pre-validation and validation of three in vitro embryotoxicity tests. These tests employ the cultivation of post-implantation whole rat embryos (WEC test), cultures of primary limb bud cells of rat embryos (micromass test, MM-Test), and cultures of a pluripotent mouse embryonic stem cell line (embryonic stem cell test, EST). In the current Validation Study each of the tests is evaluated in four laboratories under blind conditions. In an initial phase of the validation study six out of 20 test chemicals comprising different embryotoxic potential (non, weak and strong embryotoxic) were tested. The results were used to improve the prediction models (PM) for the WEC test and the MM-Test in order to identify the embryotoxic potential of test chemicals. In addition, the existing PM for the EST was evaluated using the results from testing of the initial six chemicals. The PM for the EST was developed using the results of a previous pre-validation study (Scholz et al.,1999), in which 94% of the learning sample were classified correctly. Applying this PM to the results of the initial phase of the current validation study, 80% of the experiments were classified correctly according to the embryotoxic potential of the tested chemicals in vivo. Applying the PM for the MM-Test and the WEC test that were developed during the current validation study in both tests, 79% correct classifications were achieved. Since the PM of the WEC-Test took into account only parameters of growth and development, but not cytotoxicity data, a second PM (PM2) for the WEC was developed that was improved by incorporating cytotoxicity data of the differentiated mouse fibroblast cell line 3T3 derived from the EST. This approach, which has previously never been used as an adjunct to the WEC test, resulted in an increase of correct classifications to 96%.

Effects of gestational exposure to a video display terminal-like magnetic field (20-kHz) on CBA/S mice.

Possible adverse effects of magnetic fields (MFs) on reproduction have been an open question. To verify the embryo-lethal effect of pulsed MF of the type emitted by video display terminals (VDTs) reported previously in CBA/S mice, a developmental toxicity study was conducted in animals of the same origin. Mated CBA/S mice (80-86 pregnant animals per group) were exposed to a 20-kHz MF with sawtooth waveform continuously from gestational day 0-18. The flux density of the vertical MF was 15 microT peak-to-peak (150 mG). This field was previously reported to increase the number of resorptions in CBA/S mice. On gestational day 18, the dams were killed and blood and bone marrow samples were taken for hematology and micronuclei analysis, respectively. The number of corpora lutea was counted and the content of the uterus examined. There were no statistically significant differences in maternal or fetal body weights, number of corpora lutea, implantations, resorptions, dead and live fetuses, or external and skeletal malformations. MF did not alter the number of blood cells or cause micronuclei in bone marrow erythrocytes in the dams. The mean number of resorptions was slightly but not statistically significantly, higher in the MF group than in controls. The results do not indicate marked developmental, hematological, or clastogenic effects of 20-kHz MFs.

Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing.

The pharmacokinetics of a new serotonin 5-HT2 antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg(-1) and intravenous doses of 1, 3 and 6 mg kg(-1) were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg(-1) doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45-61%. Deramciclane had a large volume of distribution (32-37 L kg(-1)) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h(-1)) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC(0-infinity) increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N-desmethyl deramciclane, was also nonlinear (p = 0.0002). At steady state deramciclane accumulated less than 2-fold during repeated administration.

Effects of low-frequency magnetic fields on fetal development in CBA/Ca mice.

Effects of alternating magnetic fields (MFs) on the embryonic and fetal development in CBA/Ca mice were studied. Mated females were exposed continuously to a sinusoidal 50 Hz (13 microT or 0.13 mT root mean square) or a sawtooth 20 kHz (15 microT peak-to-peak) MF from day 0 to day 18 of pregnancy for 24 h/day until necropsied on day 18. Control animals were kept under the same conditions without the MF. MFs did not cause maternal toxicity. No adverse effects were seen in maternal hematology and the frequency of micronuclei in maternal bone marrow erythrocytes did not change. The MFs did not increase the number of resorptions or fetuses with major or minor malformations in any exposure group. The mean number of implantations and living fetuses per litter were similar in all groups. The corrected weight gain (weight gain without uterine content) of dams, pregnancy rates, incidences of resorptions and late fetal deaths, and fetal body weights were similar in all groups. There was, however, a statistically significant increase in the incidence of fetuses with at least three skeletal variations in all groups exposed to MFs. In conclusion, the 50 Hz or 20 kHz MFs did not increase incidences of malformations or resorptions in CBA/Ca mice, but increased skeletal variations consistently in all exposure groups.

Increased resorptions in CBA mice exposed to low-frequency magnetic fields: an attempt to replicate earlier observations.

This paper has two aims. First, it reports the findings of a study on the effects of low-frequency magnetic fields on reproduction. Second, it serves as an example of an attempt to replicate the results of an experimental study in an independent laboratory and discusses some of the problems of replication studies. To try to replicate the findings of a study reporting increased resorptions (fetal loss) in mice exposed to 20 kHz magnetic fields with sawtooth waveform and to study the possible effects of 50 Hz sinusoidal fields, pregnant mice were exposed to magnetic fields from day 0 to 18 of pregnancy, 24 h per day. The flux densities of the vertical magnetic fields were 15 microT (peak-to-peak) at 20 kHz and 13 or 130 microT (root mean square) at 50 Hz. Two strains of animals were used: CBA/S mice imported from the laboratory reporting the original observations, and a closely related strain CBA/Ca. The CBA/S mice were cleaned of pathogenic microbes and parasites before they were imported into our laboratory. The magnetic field exposures did not affect resorption rate in CBA/Ca mice. In CBA/S, the frequency of resorptions was higher in the exposed mice than in the control group. However, the increase was not significantly different from either the no-effect hypothesis or the results of the original study we were attempting to replicate. Differences between the two studies and difficulties in interpreting the results are discussed. It is concluded that the results tend more to support than argue against increased resorptions in CBA/S mice exposed to the 20 kHz magnetic field. The results demonstrate that animal strain is an important variable in bioelectromagnetics research: even closely related strains may show different responses to magnetic field exposure.

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.