Diet: The Neglected Variable in Chemical Safety Evaluations

Newberne, Paul M.; Sotnikov, Alexander V.

doi:10.1177/019262339602400619

Cited by 21 publications

(21 citation statements)

References 14 publications

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“…The occurrence of tumors in the esophagus of untreated rats parallels to a considerable extent the only other case to our knowledge where taking something out of the diet, rather than adding a carcinogen, results in neoplasia. The cho line (methyl)-deficient rat develops hepatocellular carci noma [17], an event closely associated with fatty liver (steatosis) and its sequelae [18][19][20]. This will be alluded to in the discussion section.…”

Section: Tumor Incidence and Frequencymentioning

confidence: 99%

Esophageal Carcinogenesis in the Rat: Zinc Deficiency and Alcohol Effects on Tumor Induction

Newberne

Schrager

Broitman³

1997

Pathobiology

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Sprague-Dawley male rats were fed zinc-deficient or supplemented diets for 2 weeks, administered a carcinogenic dose of methylbenzylnitrosamine and observed over 20 or more weeks for effects of superimposing excess zinc or alcohol on development of esophageal tumors. In three separate experiments it was shown that (1) excess zinc offered no protection, (2) switching diets during or after carcinogen exposure pointed toward involvement of zinc in both initiation and promotion, (3) neither ethanol nor 3-methyl butanol alone affected tumorigenesis but the two combined and superimposed on a zinc deficiency resulted in a significant enhancement of neoplasia. In one group of rats fed the zinc-deficient diet only, with no carcinogen, 4 rats developed neoplasms, one of which was malignant. Cell proliferation, an integral component of zinc deficiency, appears to be an important contribution to tumor induction in this model.

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Section: Tumor Incidence and Frequencymentioning

confidence: 99%

Esophageal Carcinogenesis in the Rat: Zinc Deficiency and Alcohol Effects on Tumor Induction

Newberne

Schrager

Broitman³

1997

Pathobiology

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“…However, the elimination of these exogenous stressors has allowed other variables to affect these rodent bioassays. Over the past two decades there has been a steady increase in study-to-study variability, a lack of reproducibility, and increases in the onset and severity of spontaneous degenerative disease and tumors resulting in decreased rodent survival in chronic bioassays Duffy et al, 1989;Fishbein, 1991;Hart et al, 1995;Haseman & Rao, 1992;Keenan et al, 1992Keenan et al, , 1994aKeenan et al, , 1994bKeenan et al, , 1995aKeenan et al, , 1995bKeenan et al, , 1996Keenan et al, , 1997Lang, 1991;Newberne & Sotnikov, 1996;Rao et al, 1990;Roe, 1994;Turturro et al, 1995).…”

mentioning

confidence: 99%

“…The practice of overfeeding is largely one of caloric excess and is an example of nutritional overdosing. Ad libitum (AL) overfeeding is the most poorly controlled variable in these bioassays, and its complicating effects on the design, results, and interpretation of toxicity and carcinogenicity studies continue to be ignored by many risk assessment practitioners Hart et al, 1995;Keenan etal., 1996;Newberne & Sotnikov, 1996;Turturro etal., 1995). This is surprising, for the adverse phenomenon of AL caloric excess and its control by moderate dietary restriction (DR) have been well documented by toxicologists, pathologists, nutritionists, and gerontologists (Finch, 1990;Fishbein, 1991;Hart etal., 1995;Keenan etal., 1996;Klurfeld et al, 1989;Masoro & Austad, 1996;McDonald, 1997;McCay et al, 1935;Merry & Holehan, 1994;Rogers et al, 1993;Rose, 1991;Ross, 1976;Sohal & Weindruch, 1996;Yu, 1995;Weindruch & Walford, 1988;Weindruch, 1996;Weindruch & Sohal, 1997).…”

mentioning

confidence: 99%

“…Many evolutionary biologists, nutritionists, gerontologists, and medical scientists consider uncontrolled AL overnutrition to result in pathological aging and accelerated senescence that need to be controlled by moderate food intake (Allaben etal., 1996;Finch, 1990;Hartetal., 1995;Masoro, 1995Masoro, , 1996Masoro & Austad, 1996;McDonald, 1997;Rose, 1991;Rosenbaum et al, 1997;Yu, 1995;Weindruch, 1996). Over the past few years toxicologists and pathologists have increasingly begun to recognize that AL overfeeding is the most important uncontrolled variable in the rodent bioassay Hart et al, 1995;Keenan et al, 1996;Newberne & Sotnikov, 1996). The effects of excessive AL caloric intake adversely affect every physiological process and anatomical structure at the molecular level.…”

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confidence: 99%

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Need for dietary control by caloric restriction in rodent toxicology and carcinogenicity studies

Keenan

Laroque

Dixit

1998

Journal of Toxicology and Environmental Health, Part B

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The conditions under which laboratory animals are maintained can powerfully influence the results of toxicological studies utilized for risk assessment. Nutrition is of importance in toxicological bioassays and research, because diet composition and the conditions under which it is fed can affect the metabolism and activity of xenobiotic test substances and alter the results and reproducibility of long-term studies. It is known that ad libitum (AL) overfed sedentary laboratory rodents suffer from an early onset of degenerative disease and diet-related tumors that lead to poor survival in chronic bioassays. AL-fed animals are not well-controlled subjects for any experimental studies. Examination of study-to-study variability in food consumption, body weight, and survival in carcinogenicity studies for the same strain or stock of rodents shows tremendous laboratory-to-laboratory variability. However, a significant correlation between average food (calorie) consumption, adult body weight, and survival has been clearly established. The use of moderate dietary restriction (DR) results in a better controlled rodent model with a lower incidence or delayed onset of spontaneous diseases and tumors. Operationally simple, moderate DR significantly improves survival, controls adult body weight and obesity, reduces age-related renal, endocrine, and cardiac diseases, increases exposure time, and increases the statistical sensitivity of these expensive, chronic bioassays to detect a true treatment effect. A moderate DR regimen of 70-75% of the maximum unrestricted AL food intake is recommended as a nutritionally intelligent, well-established method in conducting well-controlled toxicology and carcinogenicity studies.

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“…Rats continued on the zinc-deficient diet for 2 months after dosing with MBN had a significantly in creased tumor incidence compared to rats fed the defi cient diet only through the dosing with MBN (groups 1 and 3: table 1), 82 vs. 31%, p < 0.01. indicating an effect both during and after carcinogen exposure, most evident in the former [6], This interpretation was reinforced by the observation that starting zinc deficiency after MBN dosing also significantly increased tumor incidence (group 9; table 1) compared to control diet ad libitum (59 vs. 31%; p < 0.01). Pair-feeding the control diet to the level for the reduced food intake or zinc-deficient rats sig nificantly reduced tumor incidence (14 vs. 31%; p < 0.01), reflecting the well-known influence of a reduced caloric effect on tumorigenesis [17,18]. In these studies, no tumors were found in organs or tissues other than the esophagus.…”

Section: Tumorigenesis St Tidiesmentioning

confidence: 69%

Esophageal Carcinogenesis in the Rat: Zinc Deficiency, DNA Methylation and Alkyltransf erase Activity

Newberne¹,

Broitman²,

Schrager³

1997

Pathobiology

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Rats fed zinc-deficient diets and given an esophageal carcinogen, methylbenzylnitrosamine, develop tumors in greater incidence and with increased frequency compared to zinc-supplemented rats. This greater susceptibility is associated with a unique esophageal lesion, parakeratosis, with markedly increased epithelial necrosis and cell proliferation. Recent studies have shown that the increased susceptibility to tumorigenesis was further associated with a number of metabolic and biochemical alterations including increased binding of the carcinogen to DNA, shifts in O⁶-methylguanine (O⁶MeG)/7-methylguanine ratios and suggestions that the promutagen O⁶MeG lesion is not repaired effectively in the zinc-deficient esophagus; the latter was not reflected in the amount of O⁶-methyltransferase activity, however. The weight of evidence supports a presumption that zinc deficiency interferes with normal DNA repair mechanisms, the nature of which is not clear. An interesting additional finding was that zinc deficiency alone was associated with esophageal tumor induction, without carcinogen, which indicates that genetic material in the zinc-deficient esophageal epithelium is damaged sufficiently, without further chemical injury, to result in loss of control of cell proliferation. Manipulation of the time of exposure to zinc deficiency and carcinogen exposure defined the initiation period as most affected by the deficiency. Furthermore, reduced carcinogen exposure (and less toxicity), along with zinc deficiency, permits development of more tumors of the endophytic type, the form more relevant to human esophageal tumors. The groundwork, as described in this paper, has now been prepared to directly address the latter issue, endophytic tumors, and the putative relation of zinc deficiency to esophageal cancer in human populations.

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Diet: The Neglected Variable in Chemical Safety Evaluations

Abstract: The objectives of this review are to alert the community of toxicologic pathologists to the types and significance of

Cited by 21 publications

References 14 publications

Esophageal Carcinogenesis in the Rat: Zinc Deficiency and Alcohol Effects on Tumor Induction

Esophageal Carcinogenesis in the Rat: Zinc Deficiency and Alcohol Effects on Tumor Induction

Need for dietary control by caloric restriction in rodent toxicology and carcinogenicity studies

Esophageal Carcinogenesis in the Rat: Zinc Deficiency, DNA Methylation and Alkyltransf erase Activity

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