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E M Faustman

Publications and source records attributed to E M Faustman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Maternal exposure to N-nitrosatable drugs as a risk factor for childhood brain tumours.

BACKGROUND: Animal models suggest that compounds containing a nitrosyl group (N-nitroso compounds (NNO)) can act as potent transplacental carcinogens. Many common drug formulations have the potential to undergo nitrosation in vivo. The association between maternal use of nitrosatable drugs during pregnancy and development of brain tumours in the offspring was examined in a SEER-based case-control study. METHODS: Maternal exposure to nitrosatable drugs during pregnancy was compared among 361 childhood brain tumour cases and 1083 matched controls recruited through random-digit dialing. RESULTS: There was no increase in risk observed for childhood brain tumours overall (OR = 1.15; 95% CI: 0.69-1.94) or for astrocytomas individually (OR = 1.16; 95% CI: 0.50-2.69). A slight elevation in risk was noted for medulloblastomas (OR = 1.47; 95% CI: 0.28-7.62) and 'other' tumours (OR = 1.27; 95% CI: 0.56-2.86), however, both estimates were based on small numbers. CONCLUSIONS: Our findings suggest that no increased risk of childhood brain tumours was associated with maternal exposure to nitrosatable drugs. The study results should be viewed with caution given the imprecision of the point estimates as well as the lack of data on specific timing and dosage of exposure and degree of nitrosatability of drugs taken.

Astrocytoma↗
PubMed1994

Dose-response assessment for developmental toxicity. I. Characterization of database and determination of no observed adverse effect levels.

Developmental toxicity risk assessment currently relies on the estimation of reference doses (RfDDTs) or reference concentrations (RfCDTS) based on the use of no observed adverse effect levels (NOAELs) and uncertainty factors. The benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. A large database of 246 developmental toxicity experiments (Segment II-type studies) representing 1825 data subsets for various endpoints was compiled for use in comparing NOAEL and BMD approaches to developmental toxicity risk assessment. This paper describes the characteristics of the database used and the estimation of NOAELs using several approaches. For each endpoint evaluated, two NOAELs were calculated using the NOSTASOT procedure (Tukey et al., 1985). The first NOAEL calculation, the QNOAEL, was based on a quantal response where a litter was defined as "affected" if one or more fetuses or implants in the litter had the endpoint of interest. The second NOAEL calculation, the CNOAEL, was based on the proportion of fetuses or implants affected within each litter and was treated as a continuous response variable. Fifty-seven percent of the 246 experiments had at least one endpoint that showed a significant trend with dose. A total of 386 data sets were significant with respect to both the quantal and continuous test of trend. An additional 44 data sets were identified with significant trend only by the quantal approach whereas 177 additional data sets were identified with significant trend tests only by the continuous approach. Thus, the continuous approach appeared to be more powerful in detecting dose-related toxicity, but the patterns detected by the two approaches differed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dose-response assessment for developmental toxicity. II. Comparison of generic benchmark dose estimates with no observed adverse effect levels.

Developmental toxicity risk assessment currently relies on the estimation of reference doses (RfDDTS) of reference concentrations (RfCDTS) based on the use of no observed adverse effect levels (NOAELS) divided by uncertainty factors (UFs). The benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. A large database of 246 developmental toxicity experiments representing 1825 endpoints related to dead implants or malformed fetuses has been compiled for use in evaluating alternative approaches to developmental toxicity risk assessment. Using this database we have compared two approaches for BMD estimation with each other and with corresponding statistically derived NOAELS. Comparisons have been based on proportion of affected litters (litters with one or more affected offspring, a quantal response variable) and on the proportion of affected offspring within each litter (a continuous response variable). A quantal Weibull model was used to calculate generic BMDs for the quantal response variable (QBMDs) and a continuous power model was used to calculate generic BMDs for the continuous response variable (CBMDs) at three levels of additional risk (10, 5, and 1%). CBMD05s (continuous benchmark doses for 5% risk) and CNOAELs (statistically derived NOAELs based on the continuous response variable) were similar, with over 98% of the data subsets having CBMD05 and CNOAEL values that differed by less than an order of magnitude. In contrast, QNOAELs tended to be greater than corresponding QBMD10s. The observed conservatism of the QBMD values relative to the corresponding CBMD values was attributed to two factors, lower maximum likelihood estimates for the quantal model and wider confidence intervals around the maximum likelihood estimates, compared to the continuous model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dose-response assessment for developmental toxicity. III. Statistical models.

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.

Animals↗
PubMed1994

Effects of methyl mercury on the cell cycle of primary rat CNS cells in vitro.

Methyl mercury (MeHg) may interfere with cell cycle progression in a number of ways, most notably through an inhibition of protein synthesis or through effects on mitotic spindle performance; both mechanisms have experimental support. Results from investigations into the effects of MeHg exposure on cell cycle progression in a primary fetal rat CNS culture are presented here. Colchicine was also investigated because it is a well-characterized mitotic inhibitor. Flow cytometric DNA content analysis was utilized to determine the cell cycle distribution histograms of control and treated cultures. In addition, a flow cytometric technique which involves the incorporation of 5-bromo-2'-deoxyuridine into newly synthesized DNA was used to discriminate between successive cell cycles. Exposure of the CNS cell cultures to MeHg (2 and 4 microM) over a period of 0-48 hr led to a G2/M-phase inhibition as determined by flow cytometric DNA content analysis. Whereas exposure to 2 microM MeHg resulted in G2/M-phase inhibition, an analysis of cell cycle progression demonstrated an inhibition of cell cycling through any phase following exposure to 4 microM MeHg; these effects occurred in the first round of cell division following plating. Exposure to colchicine (25 nM) resulted in a G2/M-phase arrest similar to that observed with MeHg (2 microM). However, a comparison of the cytotoxicity patterns between MeHg-treated and colchicine-treated cultures suggests that MeHg-induced cytotoxicity cannot be solely ascribed to G2/M-phase arrest, since at equivalent levels of G2/M-phase arrest, MeHg was more cytotoxic than colchicine. These results are consistent with the hypothesis that microtubules, and the mitotic spindle, are especially sensitive to MeHg exposure.

Animals↗
PubMed1994

Effects of styrene oxide on differentiation and viability of rodent embryo cultures.

Epidemiological investigations on the reproductive and developmental outcomes of rubber and plastic industry workers have focused on the potential developmental toxicity of styrene, an important occupational chemical, and its metabolite, styrene oxide using two in vitro culture systems: micromass cell cultures and whole embryo culture (WEC). Further, we have compared the effects of styrene oxide in both culture systems to the developmental toxicity of styrene in the micromass system. The ability of styrene oxide to affect the differentiation of rat embryo midbrain (CNS) and limb bud (LB) cells was compared to general cytotoxicity over 5 days in high-density micromass cultures. The IC50 for differentiation was 9.2 micrograms/ml (76 microM) for CNS and 6.7 micrograms/ml (56 microM) for LB. The LC50 for cytotoxicity was 9.6 micrograms/ml (80 microM) and 27.5 micrograms/ml (228 microM) for CNS and LB, respectively. The values for CNS sensitivities suggest that inhibition of differentiation is probably a consequence of high levels of cytotoxicity. In contrast, effects of styrene oxide on LB endpoints of differentiation were evident at concentration levels which had minimal effects on cell viability. Styrene alone or in the presence of an exogenous monooxygenase system had minimal effects when tested at concentrations 4-12 times the highest IC50 values seen with styrene oxide alone. In whole embryo culture experiments, styrene oxide produced growth retardation and embryo malformations (primarily neural) with an MC50 value of 20 micrograms/ml (167 microM). The LC50 value for styrene oxide was approximately 1.7-fold higher (33.2 micrograms/ml, 276 microM). Our in vitro studies suggest that further evaluations of the relationship of developmental toxicity and generalized cytotoxicity of styrene and its metabolite are needed, especially given the low concentrations at which effects were seen.

Animals↗
PubMed1994

Effects of ethylnitrosourea on expression of proto-oncogene pp60c-src and high-molecular-weight neurofilament protein in rodent embryo central nervous system cells in vitro.

Effects of exposure to ethylnitrosourea (ENU) on expression of proteins that play a role in neuronal differentiation were examined in central nervous system (CNS) micromass embryo cell cultures. ENU is a known developmental toxicant which affects neuronal development. The proteins selected were the protein product of the src proto-oncogene (pp60c-src) and high-molecular-weight neurofilament protein (NF). pp60c-src has marked increases in amount and kinase activity in neurons at the time of differentiation and NF is found in differentiated neurons. CNS micromass cultures are primary cells from Day 12 rat embryo midbrains which are plated at high density and differentiate into neurons during 5 days in culture. Proteins were quantitated by polyacrylamide gel electrophoresis separation of equal amounts of total cell protein followed by transfer to membranes, immunoblotting, and densitometric scanning of blots. Dose-dependent decreases in cell growth and differentiation were confirmed using endpoints of cell number, protein content of cultures, neutral red uptake, hematoxylin staining of differentiated cells, and levels of binding of the neurotransmitter [3H]gamma-aminobutyric acid. Concentrations which inhibited response by 50% compared to controls ranged from 232 to 455 microM ENU. Dose-related decreases in amounts of pp60c-src and NF proteins relative to total protein were seen in CNS cultures treated with ENU. Results confirm the usefulness of the micromass cultures in following chemical effects on neuronal differentiation. The effects of ENU on specific proteins associated with neuronal differentiation were shown.

Analysis of Variance↗
PubMed1992

Effects of benzimidazole analogs on cultures of differentiating rodent embryonic cells.

Micromass cell culture systems for rat embryo midbrain (CNS) and limb bud (LB) cells were employed to assess the in vitro developmental toxicity of the benzimidazole analogs, mebendazole (MBZ), thiabendazole (TBZ), and nocodazole (NCZ), in addition to the classic microtubule inhibitor, colchicine. Comparison was made to albendazole (ABZ), a previously studied benzimidazole anthelmintic. Two parameters for assessing developmental toxicity were measured: differentiation and cytotoxicity. The relative potencies of the benzimidazole analogs in the micromass system (NCZ greater than MBZ approximately ABZ much greater than TBZ) mirrored their effectiveness in an assay for in vitro inhibition of mammalian tubulin polymerization. Colchicine also exhibits a high affinity for mammalian tubulin and was a potent inhibitor of cell proliferation, chondrogenesis, and neuronal differentiation. Immunofluorescent staining of Day 1 LB cultures with a monoclonal antibody to beta-tubulin revealed that these agents elicited mitotic arrest. Many anti-tubulin agents are teratogenic in rats and their in vivo developmental toxicity may reflect perturbation of microtubular structure or function. With the exception of TBZ, these agents should be considered potential developmental toxicants since they inhibit cell growth and differentiation of micromass cultures at nanomolar concentrations.

Animals↗
PubMed1992

Effects of thallium on primary cultures of testicular cells.

The objective of this in vitro study was to examine the response of mixed cultures of Sertoli and germ cells to treatment with thallium (Tl) at the range of concentrations that, in previous studies, was shown in vivo to affect reproduction. Cultures were prepared from the testis of Sprague-Dawley rats. Cultures containing approximately 3.75 x 10(6) cells/ml were treated with Tl concentrations corresponding to 35, 7, and 1.4 micrograms Tl/g testis, estimated from protein content of cultures. Observations at 24, 48, and 72 h after treatment showed a significant release of germ cells into the culture medium that was both concentration and time dependent. Cultures treated with 35 micrograms Tl/g testis showed a threefold increase in germ-cell detachment compared with controls after only 24 h of exposure. As the treatment time increased to 48 h of exposure, even cultures exposed at the lowest Tl concentration (1.4 micrograms Tl/g testis) showed significant loss of germ cells. After 48 h, cultures exposed to 7 micrograms Tl/g testis exhibited a 2.5-fold increase in germ-cell detachment, and those exposed to 35 micrograms Tl/g testis exhibited a 10-fold increase over controls. Morphological investigations of cell cultures showed evident loss of germ cells with significant reduction in prepachytene and pachytene spermatocytes and changes in the shape of Sertoli cells. These results are in agreement with in vivo studies, in which thallium treatment at comparable exposure levels manifested its earliest toxic testicular effects in Sertoli and germ cells. They also demonstrate the usefulness of this in vitro culture technique to assess toxic testicular damage rapidly.

Animals↗
PubMed1992

Carcinogenic tobacco-specific nitrosamines are present at unusually high levels in the saliva of oral snuff users in Sudan.

Exposure to tobacco-specific nitrosamines (TSNA) has been measured in the saliva of 12 users of Sudanese oral snuff (toombak). Using GC coupled to thermal energy analysis, levels of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were measured before, during and after snuff taking. In addition, two TSNA, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), were detected in the saliva of tobacco chewers for the first time and were confirmed by GC-MS. Nine out of 10 subjects had detectable saliva levels of total TSNA before chewing (0.01-1.0 micrograms/ml) and immediately following chewing (0.1-2.6 micrograms/ml). During dipping, TSNA concentrations reached microgram/ml levels; (range; number of subjects positive) NNN: (0.6-2.1; 12/12), NAT (0.06-0.5; 2/12), NAB (0.05-1.9; 12/12), NNK (0.06-6.7; 11/12), NNAL (0.05-3.3; 11/12) and iso-NNAL (0.07-0.4; 8/12). These saliva TSNA levels, which are 10-100 times the levels previously reported, are consistent with recent observations of unusually high TSNA levels in Sudanese toombak. As several of these TSNA have been shown to be carcinogenic in animals and epidemiological studies have associated human snuff use with tumours of the oral cavity, these findings draw attention to a significant potential public health hazard.

Adolescent↗
PubMed1992

Comparative studies on the neuro- and reproductive toxicity of acrylamide and its epoxide metabolite glycidamide in the rat.

The neurotoxicity of acrylamide (AA) has been the subject of extensive studies at the morphological and functional levels in both animals and man. The concern for human exposure to monomeric AA derives partly from its extensive use in molecular biology laboratories where, in the United States alone, 100,000-200,000 persons are potentially exposed. Initial work in this laboratory aiming at the development of techniques for using hemoglobin adducts as biomarkers for human exposure to AA, revealed the formation of glycidamide as a reactive epoxide metabolite of acrylamide in the rat (Chem. Res. Toxicol. 3, 406, 1990). In rats treated with 0-100 mg/kg of AA significant dose-rate effects were observed on adduct formation by both AA and glycidamide. The high rate of formation of the metabolite, especially at low doses where approximately 60% of AA was converted to glycidamide in vivo, prompted us to investigate its potential role in the induction of neurotoxic and reproductive effects attributed to AA exposure. In initial neurotoxicological experiments, the effects of the parent compound (8-14 days, 25 and 50 mg/kg/day) and the metabolite (8-14 days, 50 and 100 mg/kg/day) were compared. While at the higher dose both compounds affected the rats' performance on the rotarod, only acrylamide had a significant effect in the hindlimb splay test, which is considered a more sensitive indicator of peripheral neuropathy. On the other hand, a stronger effect was seen for glycidamide than for AA on the male reproductive system, especially on sperm cell viability.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamide↗
PubMed1991

Effects of albendazole and albendazole sulfoxide on cultures of differentiating rodent embryonic cells.

Micromass cell culture systems for rat embryo midbrain (CNS) and limb bud (LB) cells were employed to assess the in vitro developmental toxicity of the human and veterinary anthelmintic albendazole (ABZ) and its sulfoxide metabolite (SOABZ). ABZ is reported to be teratogenic in rats, and is extensively metabolized to the sulfoxide derivative. It has been postulated that SOABZ is the reactive metabolite responsible for albendazole's developmental toxicity and anthelmintic activity in vivo. Three parameters for assessing developmental toxicity were measured: cell growth, differentiation, and cytotoxicity. CNS and LB cultures were equivalent in their sensitivities to both ABZ and SOABZ. ABZ was approximately 50-fold more potent than SOABZ. Immunohistochemical determinations of tubulin organization revealed that both ABZ and its sulfoxide metabolite elicit an accumulation of cells in the mitotic phase of the cell cycle. Since ABZ is one of the most potent agents tested in the micromass system to date, this anthelmintic should be considered a potential developmental toxicant.

Albendazole↗
PubMed1991

Unusually high levels of carcinogenic tobacco-specific nitrosamines in Sudan snuff (toombak).

The aim of these studies was to determine the levels of carcinogenic tobacco specific nitrosamines (TSNA) in Sudanese oral snuff (toombak) as recent retrospective epidemiological studies suggested an association between the use of toombak and subsequent development of oral cancer. We have analyzed the TSNA levels in 20 samples of Sudanese toombak, of four different quality levels, collected from five different vendors. Using GC coupled with thermal energy analysis, four TSNA were quantified in snuff extracts: N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Unusually high levels of these TSNA (mean; range, mg/g snuff, dry wt) were detected; NNN (1.13; 0.50-3.08); NAT (0.08; 0.02-0.29); NAB (0.22; 0.02-2.37); and NNK (2.31; 0.62-7.87). Previously, the highest levels of NNN and NNK reported in any snuff were 0.154 and 0.014 mg/g dry wt respectively. In comparison, the levels in Sudanese toombak were up to 20 and 560 times higher respectively. As the public health implications of these findings are significant, attempts should be made to reduce exposure to TSNA in oral snuff users in Sudan.

Carcinogens↗
PubMed1990

Chemically induced growth inhibition and cell cycle perturbations in cultures of differentiating rodent embryonic cells.

Ethylnitrosourea (ENU) is a proven animal teratogen, although the mechanism of its developmental toxicity is unknown. The micromass rat embryo midbrain (CNS) and limb bud (LB) cultures were used in an effort to determine potential mechanisms by which ENU may exert its teratogenic effect. When cultured at high cell densities, both cell types undergo several rounds of replication while differentiating into discrete foci of neuronal cells and chondrocytes, respectively. Differentiation was monitored after 5 days by staining with hematoxylin (CNS) and alcian blue (LB). Our objectives were to (1) apply flow cytometry technology to the micromass cultures and (2) determine how ENU disrupts the normal growth, differentiation, and cell cycling of these cultures. Dose-dependent decreases in cell attachment and viability were observed in the first 24 hr after ENU exposure. Exposed cultures also exhibited dose-dependent growth inhibition over 5 days in culture as determined by cell counts. Flow cytometric cell cycle analysis of treated cultures revealed a dose-related accumulation of CNS cells in late G1/early S. Treated LB cells also displayed dose-related cell cycle changes with cells accumulating throughout the S phase. The concentration-dependent changes in both the CNS and the LB cell cycle profiles were observed in the attached cell populations which had greater than 94 +/- 3% viability at all ENU concentrations tested. This suggests that flow cytometric analysis allowed description of cellular alterations that would have been overlooked if only cell viability had been examined. Our examinations suggest that the effects of ENU on cell differentiation are related to its early effects on cell attachment, cell cycling, and cell proliferation.

Animals↗
PubMed1989

In vitro developmental toxicity of five direct-acting alkylating agents in rodent embryos: structure-activity patterns.

Five direct-acting alkylating agents were examined qualitatively and quantitatively for their ability to produce developmental toxicity in rodent postimplantation embryos. These agents were structurally related and were capable of donating either a methyl (methylnitrosourea, MNU; methylnitronitrosoguanidine, MNNG; methyl methanesulfonate, MMS) or ethyl (ethylnitrosourea, ENU; ethyl methanesulfonate, EMS) group to nucleophiles. These agents' reactivities were known to differ. In day 10 rat embryos in vitro a single, 2-hour exposure was shown to be sufficient to elicit dose-dependent increases in embryo lethality and malformations. Qualitatively, the patterns of embryo malformations reported in treated embryos paralleled those observed in in vivo studies, especially in regard to adverse effects on central nervous system and craniofacial systems. Quantitatively, the order of potency of these agents in vitro was: MNNG greater than MNU greater than ENU greater than MMS greater than EMS. In vivo studies reported a different order of potency. In vitro, methylating agents were consistently more potent than ethylating agents. Other chemical properties such as nucleophilic reactivity or half-life under physiological conditions could not explain observed potency relationships. Future investigation of other chemical properties of these agents such as specific alkylation and carbamylation reactivities may expand these initial structure-activity observations.

Alkylating Agents↗
PubMed1989

Lipid mediator production by post-implantation rat embryos in vitro.

The production of inflammatory lipid mediators by post-implantation rodent embryos was examined in this study. Explanted day 10 rat embryos, either intact or after homogenization, were cultured for 3 hr in vitro and the resulting culture medium and embryonic tissue were assessed for eicosanoids and platelet-activating factor (PAF). The rank order of cyclooxygenase arachidonate products produced by intact embryos was as follows: 6-keto-PGF1 alpha much greater than congruent to PGF2 alpha congruent to TXB2. No lipoxygenase products of arachidonic acid metabolism were detected by either high performance liquid chromatography or radioimmunoassay. PAF production was detectable in embryonic cultures. Homogenization of rat embryos prior to in vitro culture enhanced eicosanoid and PAF production from 2.1-6.9 fold over intact embryos. These findings demonstrate the extent of lipid metabolism by early post-implantation rat embryos and support the concept that potent lipid mediators of inflammation generated by the conceptus may play a role in both the initiation and maintenance of pregnancy.

Alprostadil↗
PubMed1989

Nitrosatable drug exposure during pregnancy and adverse pregnancy outcome.

Recent investigations have suggested that drugs that are amines can undergo endogenous or exogenous nitrosation reactions to form N-nitroso compounds. These compounds have been extensively characterized in animal models as carcinogens, mutagens and teratogens. In order to examine the possible effects of exposure to nitrosatable drugs during gestation on pregnancy outcome, data were utilized from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. Pregnancy outcomes for 6061 pregnancies in which the mother ingested a drug known to undergo nitrosation were compared with 6921 randomly sampled pregnancies without such exposure. The major outcome factors of interest were birth defects, fetal, neonatal and infant death and birthweight. Our findings suggest that no significant increases in risk of fetal, neonatal and infant death or low birthweight were associated with nitrosatable drug exposure during pregnancy. However, the risk of a tumour in the offspring of exposed mothers was increased (relative risk, RR = 2.29; 95% Cl 0.99-5.26). Increases in relative risk of major malformations was also observed and this increase was greater when exposure during the first four months of pregnancy was examined separately (RR = 1.33; 1.11-1.58). There were specific individual malformations that were observed to have increased relative risks (for example: eye malformations, hydrocephaly, craniosynostosis and meningomyelocoele/meningocoele) but interpretation was difficult due to multiple comparisons and some of these observations were associated with wide confidence intervals. These types of adverse pregnancy outcomes were consistent with animal study outcomes.

Abnormalities, Drug-Induced↗