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Multiple Chemical Exposures: Synergism Vs. Individual Exposure Levels.
N. R. Haghdoost, L. Newman, E. Johnson
Published 1997 · Biology, Medicine
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Exposure to single chemicals is known to produce congenital malformations in both pregnant animals and humans exposed at sufficiently high intensity. However, real life involves multiple, simultaneous exposures. Using as a database the 43 multiple chemical exposure studies located by Nelson (Teratology 49:33-71; 1994) where synergism was reported, we explored the degree to which such concerns may be realistic from the viewpoint of the current standard developmental toxicity safety evaluation process. Focusing on the assessment of the lowest tested dose of a given agent participating in synergistic activity as compared to its threshold level for eliciting toxicity when administered alone, we found that while the availability of adequate data was limited, all cases, with the possible exception of one, demonstrated synergistic toxic expression only when at least one, and usually both, compounds were used at or above their individual threshold for toxicity. These findings suggest that in animals such phenomena of synergistic chemical interactions are likely to occur only when at least one and more likely both agents are administered at or above their individual threshold for toxicity. To the extent animal studies are predictive of human developmental hazards due to single chemical exposures, available data do not establish multiple chemical exposures as a major human developmental concern.
This paper references
Effect of phenobarbital and SKF 525A pretreatment on diphenylhydantoin teratogenicity in mice.
R. Harbison (1970)
Studies on the teratogenic effects of different oral preparations of caffeine in mice.
M. M. Elmazar (1982)
Teratogenic effect of cocaine and diazepam in CF1 mice.
S. Mehanny (1991)
Enhancement of murine phenytoin teratogenicity by the gamma-glutamylcysteine synthetase inhibitor L-buthionine-(S,R)-sulfoximine and by the glutathione depletor diethyl maleate.
M. Wong (1989)
Differential reactivity of the myoendometrial and placental vasculatures: adrenergic responses.
F. C. Greiss (1972)
Acetazolamide teratogenesis in Wistar rats: potentiation and antagonism by adrenergic agents.
K. Ugen (1986)
Teratogenic effects of a lipophilic cationic dye rhodamine 123, alone and in combination with 2-deoxyglucose.
R. Hood (1988)
Experimental studies on nicotine absorption in rats during pregnancy. 3. Effect of subcutaneous injection of small chronic doses upon mother, fetus, and neonate.
R. F. Becker (1968)
Embryotoxic and teratogenic effects of interaction of cadmium and lindane in rats.
D. K. Saxena (1986)
Metal-salt potentiation of salicylate-induced teratogenesis and behavioral changes in rats.
C. Kimmel (1974)
On the Subject of Incorrect Terminology
E. Johnson (1994)
Production of fetal rat malformations by norchlorcyclizine and chlorcyclizine after intrauterine application.
A. L. Wilk (1969)
Interactions in developmental toxicology: a literature review and terminology proposal.
B. K. Nelson (1994)
TCDD embryotoxicity in the mouse may be enhanced by beta-naphthoflavone, another ligand of the Ah-receptor.
E. Hassoun (1982)
The relationship of embryotoxicity to disposition of 2-methoxyethanol in mice.
R. Sleet (1988)
Teratogenic effect of maternal zinc deficiency and its co-teratogenic effect with cadmium.
F. Sato (1985)
Ciba Foundation symposium on congenital malformations
G. Wolstenholme (1960)
The effects of various levels of dietary protein on retinoic acid-induced teratogenicity in rats.
G. Nolen (1972)
Incidence and potentiation of external and internal fetal anomalies resulting from chlordiazepoxide and amitriptyline alone and in combination.
B. Beyer (1984)
Teratogenic action of the thyroid stimulating hormone and its interaction with trypan blue.
A. Beaudoin (1966)
Retinoic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin selectively enhance teratogenesis in C57BL/6N mice.
L. Birnbaum (1989)
Teratogenicity of combinations of sodium dichromate, sodium arsenate and copper sulphate in the rat.
R. W. Mason (1989)
Combined embryotoxic action of toluene, a widely used industrial chemical, and acetylsalicylic acid (aspirin).
G. Ungváry (1983)
Potentiation of acetazolamide induced ectrodactyly in SWV and C57BL/6J mice by cadmium sulfate.
M. H. Kuczuk (1984)
Potentiation of acetazolamide induced ectrodactyly in Wistar rats by vasoactive agents and physical clamping of the uterus.
K. Ugen (1985)
Teratogenic effects on the CD-1 mouse embryo exposed to concurrent doses of ethanol and aspirin.
J. F. Guy (1986)
Effects of pretreatment with SKF-525A, N-Methyl-2-thioimidazole, sodium phenobarbital, or methyl cholanthrene on ethylenethiourea-induced teratogenicity in rats.
K. Khera (1981)
Teratogenic effects of combined administration of ethylenethiourea and nitrite in mice.
S. Teramoto (1980)
Alcohol enhancement of marihuana-induced fetotoxicity.
E. Abel (1985)
Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 1. Teratogenicity of ethanol and acetaldehyde.
P. Blakley (1984)
Dosage – Response Curves for the Teratogenic Activity of Trypan Blue
F. Beck (1964)
Teratogenic potency of TCDD, TCDF and TCDD-TCDF combinations in C57BL/6N mice.
H. Weber (1985)
TERATOGENIC INTERACTION OF CHEMICAL AGENTS IN THE RAT
J. Wilson (1964)
Embryotoxic effect of cadmium on rats upon oral administration.
L. Machemer (1981)
Interaction of dietary zinc, genetic strain, and acetazolamide in teratogenesis in mice.
R. M. Hackman (1983)
Potentiation of teratogenesis.
E. Ritter (1984)
Toxicity of copper salts in hamster embryonic development.
V. Ferm (1974)
Effect of lindane on pregnancy in the rabbit and rat.
A. Palmer (1978)
The interaction of chemicals during pregnancy: an update.
R. Skalko (1983)
Ethanol-induced limb defects in mice: effect of strain and Ro15-4513.
E. F. Zimmerman (1990)
Problems in Developmental Toxicology Caused by Incorrectly Used Terminology1
M. Christian (1993)
Pharmacological studies on the potentiation of phenytoin teratogenicity by acetaminophen.
J. Lum (1986)
Embryotoxic and teratogenic action of 5-hydroxytryptamine: mechanism of action in the rat.
P. Marley (1967)
Synergistic interaction of 2,3,7,8,-tetrachlorodibenzo-p-dioxin and hydrocortisone in the induction of cleft palate in mice.
L. Birnbaum (1986)
Effects of protein deficiency on the teratogenicity of cytochalasins in mice.
J. Singh (1987)
Potentiation of chemically induced cleft palate by ethanol ingestion during gestation in the mouse.
M. Lee (1985)
Embryotoxic effects of benzene and its methyl derivatives: toluene, xylene.
A. Hudak (1978)
Potentiation of ribavirin-induced teratogenesis by natural purines.
C. Willhite (1978)
Potentiating effect of caffeine on the teratogenicity of acetazolamide in C57BL/6J mice.
S. Beck (1991)
Attenuation of 2-methoxyethanol and methoxyacetic acid-induced digit malformations in mice by simple physiological compounds: implications for the role of further metabolism of methoxyacetic acid in developmental toxicity.
F. Welsch (1987)
Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice.
T. Nakatsuka (1983)
Potentiating effects of caffeine on teratogenicity of alkylating agents in mice.
T. Fujii (1983)
Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine.
E. Ritter (1987)
Effect of Sodium Nitrilotriacetate on Toxicity, Teratogenicity, and Tissue Distribution of Cadmium
LEWIS G. Scharpf (1972)
Potentiative interactions between caffeine and various teratogenic agents.
E. Ritter (1982)
Enhancement of chlorcyclizine teratogenicity in the rat by coadministration of calcium chelating agents.
A. L. Wilk (1978)
Effects of phorone and/or buthionine sulfoximine on teratogenicity of 5-fluorouracil in mice.
M. Naya (1990)
Influence of various levels of hypervitaminosis A and zinc deficiency on teratogenesis and DNA synthesis in the rat.
C. Eckhert (1979)
Modification of the teratogenicity and mutagenicity of cyclophosphamide with thiol compounds.
B. Hales (1981)
Teratological experiments with ergotamine in mice, rats, and rabbits.
J. Grauwiler (1973)
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Contrôle des insectes nuisibles de la famille des coléoptères
Gerson Graser (2011)
Toxic Effects of Chemical Mixtures
Harold I. Zeliger (2003)
Advances in risk assessment and communication.
B. Goldstein (2005)
Effect of co-administration of retinoids on rat embryo development in vitro.
H. Ritchie (2003)
Interaction profile for lead, manganese, zinc, and copper.
N. Roney (2004)
Effects of prenatal exposure to chronic mild stress and toluene in rats.
K. Hougaard (2005)
Interactions between Occupational and Environmental Factors in Toxicology, Hazard Evaluation and Risk Assessment
J. Gomes (2009)
Interactive effects of cadmium and all-trans-retinoic acid on the induction of forelimb ectrodactyly in C57BL/6 mice.
G. Lee (2006)
Developmental toxicity of combined ethylbenzene and methylethylketone administered by inhalation to rats.
A. Saillenfait (2006)
Retracted: Maternal and early life stress effects on immune function: relevance to immunotoxicology
D. Bellinger (2008)
Interactions in developmental toxicology: combined action of restraint stress, caffeine, and aspirin in pregnant mice.
M. Colomina (2001)
Enhancement of developmental toxicity effects of chemicals by gestational stress. A review.
K. Hougaard (2007)