Polycystic Kidney Disease Induced in F1 Sprague-Dawley Rats Fed para-Nonylphenol in a Soy-Free, Casein-Containing Diet

J. R. Latendresse*,1, R. R. Newbold{ddagger}, C. C. Weis{dagger} and K. B. Delclos{dagger}

* Pathology Associates International, National Center for Toxicological Research, Jefferson, Arkansas 72079; {dagger} Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas; and {ddagger} Developmental Endocrinology Section, Reproductive Toxicology Group, Laboratory of Toxicology, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Received December 7, 2000; accepted February 20, 2001


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
para-Nonylphenol (NP; CAS #84852–15–3), an alkylphenol with a 9-carbon olefin side chain, is widely used in the manufacture of nonionic surfactants, lubricant additives, polymer stabilizers, and antioxidants. Due to its wide commercial use and putative endocrine activity in humans and wildlife, the NTP elected to assess its effects on reproduction in multigenerational studies. To avoid known estrogenic activity of phytoestrogens in soy and alfalfa, a soy- and alfalfa-free, casein-containing diet was used in a range-finding study to determine the doses of NP to be tested further. NP was administered to Sprague-Dawley rats in the diet at 0, 5, 25, 200, 500, 1000, or 2000 ppm to F0 dams beginning on gestation-day 7. The F1 pups were weaned at postnatal day (PND) 21, and their exposure via diet was continued at the same dose level as their respective dams. Pup weights from birth through weaning were not significantly different from controls in any dose group, but the average weight of both sexes was significantly less compared to controls, beginning with the PND 28 weighing. The F1 rats were sacrificed on PND 50 (n = 15, 3 pups of each sex from 5 litters for all dose groups). Terminal body weights of males and females in the 2000-ppm dose group were 74% and 85% of controls, respectively. Severe polycystic kidney disease (PKD) was present in 100% of the 2000 ppm-exposed male and female rats. At 1000 ppm, 67% of males and 53% of females had mild to moderate PKD versus none of either sex in the control and lower-dose groups. The no-adverse-effect level (NOAEL) for PKD was determined to be 500 ppm. Previous studies with comparable duration and route of exposure, but using soy-containing diets, reported either no or only mild PKD at 2000 ppm NP. We conclude that the renal toxicity of NP is highly dependent on the diet on which the animals are maintained. The potential interaction of diet and test compounds on nonreproductive as well as reproductive endpoints should be considered when contemplating the use of special diets formulated to minimize exogenous "hormone" content for the study of the effects of putative endocrine disruptive chemicals.

Key Words: polycystic kidney; nonylphenol; soy-free diet; endocrine disruptor.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nonylphenol (NP; CAS # 84852–15–3), an alkylphenol with a 9-carbon olefin side chain, is widely used in the manufacture of nonionic surfactants, lubricant additives, polymer stabilizers, and antioxidants (Gilbert et al., 1986Go; Naylor, 1992Go). NP has weak estrogenic activity (Dodds and Lawson, 1938Go; Shelby et al., 1996Go; Soto et al., 1991Go). Due to its wide commercial use and putative endocrine activity in humans and wildlife, the NTP elected to assess its effects on reproduction in a 5-generation study designed to evaluate components of the "endocrine disruptor hypothesis." These include the potential for magnification of subtle reproductive effects over multiple generations, the importance of exposure windows, and whether effects are reversible or are imprinted to carry over across generations (Delclos and Newbold, 1997Go). We report here on a range-finding study to determine the doses of NP to be further tested in the multigeneration assay. The focus of this range-finding study was on reproductive tract effects. One aspect of this protocol that differs from the majority of other studies that have been conducted with nonylphenol and other endocrine-active compounds is the use of a soy- and alfalfa-free diet to avoid known estrogenic activity of isoflavones in soy and other phytoestrogens such as coumestrol in alfalfa. While the recent studies of nonylphenol toxicity have been focused on endocrine and reproductive endpoints, mild renal toxicity was reported in a recent multigeneration assay utilizing dietary concentrations up to 2000 ppm (Chapin et al., 1999Go). We describe here unanticipated strong renal toxicity of nonylphenol encountered over a similar dose range under our experimental conditions.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Test material.
NP (CAS # 84852–15–3) was obtained from Schenectady International, Inc. (Schenectady, NY). The purity of the compound was determined by chromatography to be greater than 95%. Homogeneity and stability of the NP in the 5-ppm mix were found to be within the tolerance limits (± 10% of target dose) for up to 30 days.

Feed.
The genistein and daidzein levels in NIH-31 and 5K96 rations used at NCTR were analyzed and reported by Doerge et al. (2000). The soy- and alfalfa-free diet, designated 5K96, was obtained from Purina Mills, Inc. (St. Louis, MO), and was sterilized by irradiation prior to shipment to NCTR. This soy- and alfalfa-supplemented diet, formulated for this study by Purina, was a modification of the NIH-31 diet used as the standard animal feed at NCTR, which had levels of 31.9 ± 3.9 µg/g of genistein and 30.4 ± 3.1 µg/g daidzein, much lower than other widely used commercial chows. 5K96 had the soy and alfalfa proteins replaced by casein and the soy oil replaced by corn oil. The vitamin mix was adjusted to account for losses during irradiation. This diet meets the nutrient specifications for NIH-31, and has a nearly identical amino acid composition and energy content. Assay of 5K96 indicated genistein and daidzein contents of 0.54 ± 0.31 and 0.48 ± 0.31 µg/g, respectively (Doerge et al., 2000Go), approximately 60-fold lower than NIH-31.

Animal husbandry.
Sprague-Dawley (CD) rats (NCTR Strain Code 23) were utilized. Temperature and humidity in the animal room were maintained at 23 ± 3°C and 50 ± 20%, respectively. A 12-h light/dark cycle was used, and the room received 10–15 air changes per hour. Pregnant females were housed singly with their litters in polycarbonate cages on standard hardwood-chip bedding (PJ Murphy, Montville, NJ). Weaned F1 pups were housed, 2 of the same sex to a cage, until sacrifice at postnatal day (PND) 50. Dosed feed and micropore-filtered tap water were provided ad libitum.

Experiment design.
Ten date-mated, vaginal plug-positive females were assigned to each dose group to ensure 5 litters per treatment. Data on all litters (size, weight, percent alive, sex ratio) were collected after birth, and 5 dams and litters from each treatment group were randomly selected for continuation on the experiment. The females (F0) were started on the 5K96 ration 2 weeks prior to breeding and randomly assigned to each group on day 6 of gestation (GD 6). NP was fed in the diet at 0, 5, 25, 200, 500, 1000, or 2000 ppm, beginning on GD 7. Body weights and feed consumption of the dams were measured daily from the start of dosing through parturition and weekly thereafter. Feed consumption measurements were based on feeder weights before and after the exposure period, and they reflect both consumption and spillage. F1 litters were randomly standardized to 4 males and females each on PND 2. Pup body weights were recorded on PND 4 and 7, and weekly thereafter until PND 50. Feed consumption was measured weekly after weaning. The F1 pups were weaned at PND 21, and their exposure was continued at the same dose level in the feed as their respective dams received. The F1 rats were sacrificed on PND 50 (n = 15, 3 animals per sex from each of the 5 litters in each dose group).

Pathology.
At study termination, the F1 rats were weighed, euthanized by exposure to carbon dioxide, and a complete necropsy was performed. All protocol-specified tissues (adrenal glands, bone and marrow, heart, kidneys, liver, lung, mammary gland, spleen, thymus, thyroid glands, ureter, urethra, urinary bladder, and reproductive tract and accessory glands, and gross lesions) were examined, removed, and preserved in either Bouin fixative or 10% neutral-buffered formalin. All protocol-specified tissues were examined microscopically in the high-dose and control groups, initially, followed by examination of the urogenital tissues and accessory sex glands for potential endocrine disrupting effects, proceeding in descending order of dose. Thus, the tissues designated for microscopic examination from control and dose groups were trimmed, processed, embedded in Tissue Prep II, sectioned at 4–6 microns, mounted on glass slides, and stained with hematoxylin and eosin or periodic acid-Schiff (PAS) and hematoxylin. As a result of the pathological assessment of the high-dose group, the kidney was unexpectedly identified as a target tissue. Therefore, kidneys from the intermediate doses were also processed in a like manner and examined microscopically. Renal cysts were subjectively graded: 4 (severe), numerous large cystic tubules uniformly distributed in the outer medulla and/or cortex (M/C) from one pole to the other in a longitudinal section of kidneys; grade 3 (moderate), similar to grade 4, but slightly fewer cysts; 2 (mild), approximately 4–10 cysts in the M/C; or 1 (minimal), 3 or fewer cysts.

Statistical analysis.
Daily and weekly body weights and feed consumption were analyzed by analysis of variance, using a mixed models approach to repeated measures. For the F1 generation, the statistical model included dose as a fixed factor and litter nested within dose as a random factor to account for possible litter effects. Litter weights were analyzed by analysis of covariance, with litter size and percent males as covariates. Dunnett's test was used to make comparisons between control and treatment groups. Histopathology data were analyzed for NP effects on lesion incidence and severity by the Jonckheere-Terpstra test (Hollander and Wolfe, 1973Go). Williams's modification of Shirley's test (Williams, 1986Go) was used to compare dosed groups to control. All statistical tests were made at the p = 0.05 level.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Body Weights and Feed Consumption
Dam feed consumption during pregnancy showed a decreasing linear trend at early times (gestation days 8–10, 12–14, and 17) and Dunnett's test showed only the 2000-ppm dose group to be significantly lower (30–40%) than controls on gestation days 8, 9, 12, and 13 (data not shown). Dam body weights showed a significant decreasing linear trend from GD 12–21. Only the 2000-ppm dose group differed significantly from the control group (10% lower), and only on GD 21 (data not shown). Total feed consumption and body weight gains during pregnancy were significantly lower than control in both the 1000-ppm and 2000-ppm groups (data not shown). There were no differences in the body weights or feed consumption of the dams after parturition, until sacrifice at the time that the litters were weaned. Nonylphenol treatment had no effect on gestation time, litter weight at birth, or on other litter parameters (Table 1Go). Body weights of male and female pups did not differ significantly from controls up to the time of weaning, after which the high-dose group of both sexes had significantly lower body weights than controls for the remainder of the experiment (Fig. 1A and 1BGo). At later time points, both male and female pups in the 200-ppm dose group had body weights significantly greater than controls (Fig. 1Go). Pup feed consumption was also generally lower than controls in the high-dose group, with significant differences from controls in pairwise comparisons, as shown in Figures 2A and 2BGo. Nonylphenol intake at various stages of the experiment, as calculated from feed consumption and body weight data, is shown in Table 2Go. The mean daily dose of NP consumed by the dams at various experimental stages was approximately 50% lower during pregnancy when compared to the lactation period. The mean daily dose for both sexes of pups from PND 21 to 50 was comparable to the NP intake of the dams during lactation. Terminal body weights of the males and females exposed to 2000 ppm were 74 and 85% of controls, respectively (Fig. 3Go). This represents a significantly reduced weight gain for both sexes.


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TABLE 1 Fertility and Litter Data for Dams Treated with Dietary NP from GD 7 to Parturition
 


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FIG. 1. Growth curves of F1 males (A) and females (B) fed the indicated doses of p-nonylphenol. Asterisks mark samples significantly different from controls at the same time point: *p < 0.05; **p < 0.01; ***p < 0.001. Control line is bolded. Asterisks below the line are associated with the 2000-ppm dose group, while those above the line are associated with the 200-ppm dose group.

 


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FIG. 2. Feed consumption of F1 males (A) and females (B) fed the indicated doses of p-nonylphenol. Asterisks mark samples significantly different from controls at the same time point: *p < 0.05; **p < 0.01; ***p < 0.001. Control line is bolded. All asterisks are associated with the 2000-ppm-dose group.

 

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TABLE 2 Mean (range) Daily Dose of NP Consumed at Various Experiment Stages (mg/kg body weight/day)
 


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FIG. 3. Terminal body weights. Means ± SEM; *significantly different from control at p <= 0.05; ***significantly different from control at p <= 0.001.

 
Microscopic Evaluation of Kidneys of F1 Animals
All the male and female rats in the 2000-ppm group had severe polycystic kidney disease (PKD; Table 3Go, Figs. 4 and 5GoGo). The disease of moderate to marked severity was characterized by numerous large cystic tubules, often uniformly distributed from one pole to the other. The outer stripe of the outer medulla was most markedly affected, but cysts extended deeper into the inner stripe of the outer medulla, and into the superficial cortex, along the medullary rays. The tubules often contained necrotic epithelial cells and/or neutrophils. There were patchy areas of mild to marked chronic interstitial nephritis and foci of degenerative and regenerative tubules. Five of 15 male rats (33%) and 4 of 15 females (27%) in the 1000-ppm groups manifested a moderate effect, while the incidence of mild PKD in male and female rats was 34% and 26%, respectively.


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TABLE 3 Incidence of Polycystic Kidney Disease (PKD)
 


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FIG. 4. Kidney from a male F1 SD rat exposed to 2000 ppm of p-nonylphenol in a soy-free, casein-containing diet. Severe polycystic kidney disease; magnification x9.5, H&E stain.

 


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FIG. 5. Kidney from a female F1 SD rat exposed to 2000 ppm of p-nonylphenol in a soy-free, casein-containing diet. Severe polycystic kidney disease; magnification x9.5, H&E stain.

 
Nephrocalcinosis was also observed at high incidences (73–100%) in the female rats in both treatment and control groups alike. Minimal mineralization was also present in the male rats in the 500-ppm group (5/15), 1000-ppm group (12/15), and 2000-ppm group (6/15). These incidences were significantly different (p < 0.001) from the controls (0/15).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nonylphenol treatment decreased feed consumption and body weight gain of dams during pregnancy in the 2000-ppm dose group, and total body weight gain during pregnancy was also reduced in the 1000-ppm dose group, but litter parameters were not affected by treatment. The pups showed decreased body weights and feed consumption that were significant in the high-dose group only after weaning. These results are generally consistent with results from a parallel feeding study with nonylphenol that was designed to evaluate effects on sexually dimorphic behaviors (Ferguson et al., 2000Go). Factors that could have contributed to the pattern of decreased food consumption and lower body weight observed include palatability of nonylphenol, a putative "estrogen effect," and acquired renal disease. Further studies would be required to address each of these as potential contributors, incorporating such designs as paired feeding and time-course exposures.

There are reports in the literature where semisynthetic, soy-free diets fed to rats and mice genetically predisposed to PKD, without further treatment, resulted in more severe PKD when compared to rations containing soy (Ogborn et al., 1998Go; Tomobe et al., 1998Go). To our knowledge, the Sprague-Dawley rat has no recognized genetic or other predisposition for PKD. The control rats (males 53% and females 67%) in our study manifested one to a few tubular cysts (minimal) in or near the region of the outer medulla or corticomedullary junction. Some rats in dose groups 5-ppm to 1000-ppm also had minimal cysts with incidences comparable to or lower than the control group. This raised concern that the soy-free diet alone in our study could have caused some PKD. After additional consideration, these cysts were interpreted as incidental, because the results of a 6-month feeding study comparing standard NIH-31 diet (soy-containing) with 5K96, which were not significantly different, showed less than a 10% incidence of cysts in both the parental generation (at 6 months) and their offspring (at PND 65) fed 5K96 (unpublished data).

Recently, other toxicologic studies of NP administered at comparable doses and longer exposure intervals were reported with minimal to mild renal cyst formation (Chapin et al., 1999Go) or no renal cyst formation (Cunny et al., 1997Go). Unlike our study, in both of these reports rats were fed diets containing soy. Earlier studies comparing the renal toxicity of butylated hydroxytoluene (Meyer et al., 1978Go) and biphenyl (Sondergaard and Blom, 1979Go) fed in either a semisynthetic diet (casein as protein source) or commercial chow, reported significantly less severe PKD when the compound was administered in the commercial chow. The protein source of the commercial diets was not specified. The authors concluded that diet has a significant impact on the renal toxicity of these compounds. Soy-induced amelioration of PKD in rodent strains used as models to study this disease has recently been reported (Aukema et al., 1999Go; Ogborn et al., 1998Go; Tomobe et al., 1998Go). These authors speculate on a number of factors that may contribute to the apparent protective effect of soy, including estrogenic effects, enzyme inhibition, fatty acid metabolism, and amino acid profiles. Interestingly, supplementation (500 ppm) of a casein-based diet with genistein, an estrogen-active isoflavone, did not reduce PKD in a mouse model (Tomobe et al., 1998Go). Recent feeding studies in our laboratory using an essentially identical experiment design and the same diet (5K96) used to test NP, but testing genistein (up to 1250 ppm) or ethinyl estradiol (up to 200 ppb) did not cause PKD in CD rats (unpublished data). These results underline the fact that the soy-free diet itself does not induce PKD in the CD rats used in our studies, which are not genetically predisposed to PKD.

NP and/or its metabolites may be able to cause some renal cysts with little or no dietary influence, which may have more relevance to human exposure. Nonylphenol has been reported as an air pollutant (2.2–70 ng/m3) in the coastal atmosphere of New York and New Jersey (Dachs et al., 1999Go). Furthermore, alkylphenolic chemicals approximating 1 µg/l have been detected in drinking water (Clark et al., 1992Go), close to the National Research Council (NRC) estimate of potential human exposure of 0.7 µg nonylphenol through drinking water (NRC, 1999). However, in the present study, the dietary doses that caused PKD in Sprague-Dawley rats were much higher than these likely human exposures.

Chapin et al. (1999) have observed mild renal cyst formation in rats fed NP in a more conventional soy-containing diet. NP and some of its derivatives are excreted by the kidney (Drotman, 1980Go; Knaak et al., 1966Go) which may deliver a significant dose to the target site, potentially from both blood and urine. Kidney in humans (Concolino et al., 1993Go) and experimental animals have estrogen receptors (Hamilton et al., 1975Go; Li and Li, 1996Go). An estrogen receptor-mediated effect on tubular epithelial cell proliferation has been proposed as a potential cause of acquired cystic kidney disease (Concolino et al., 1993Go). It is conceivable that receptor binding by NP could activate epithelial estrogen receptors, secondarily causing cystic tubules, due to cell proliferation resulting in tubular blockage. However, as noted above, neither genistein nor ethinyl estradiol induced PKD under identical experimental conditions where body weight gain depression and estrogenic actions of these compounds were clearly evident (unpublished data).

Mineralization of the renal tubule epithelium is a well known estrogen-induced effect in rats. This condition has been reviewed (Ritskes-Hoitinga and Beynen, 1992Go). In contrast to females, nephrocalcinosis is an uncommon spontaneous lesion in young male CD rats. In females, endogenous estrogens cause the condition, in part. Exogenous estrogen has been reported to cause similar mineralization in males, apparently resulting from an alteration in calcium and phosphorus homeostasis (Ritskes-Hoitinga and Beynen, 1992Go), and we have observed similar effects of genistein and ethinyl estradiol in experiments identical in design to those described here (unpublished data). Because of the reported weak estrogenic activity of NP, it is possible that the minimal mineralization observed in the 3 male groups exposed to the highest doses was an "estrogenic" effect of NP on kidney tubules. This seems more plausible than the possibility that it was a sequela of tubular epithelial necrosis associated with the toxicity of the NP-dietary interaction (e.g., PKD), because severe PKD occurred in 100% of the 2000-ppm group, but mineralization was observed in only 40% of the same group. Furthermore, mineralization was present the 500-ppm group that, like the control and the 3 other lower-dose groups, did not have PKD. In addition, Chapin et al. (1999) also noted mineralization of renal tubules in males at doses as low as 200-ppm NP under conditions where cysts or tubular dilatation were not reported. In addition to the previously noted difference in diets, the study of Chapin et al. (1999) differed from ours in that animals were older at the time of necropsy and had been exposed to treatment for a longer period.

NP has other effects that are apparently not mediated by cytosolic or nuclear estrogen receptors. NP and other alkylphenols have been shown to inhibit intracellular calcium (Ca) pumps in skeletal and smooth muscle and rat testis (Michelangeli et al., 1990Go, 1996Go; Orlowski and Champeil, 1991Go; Ruehlmann et al., 1998Go). Alterations of normal cytosolic Ca homeostasis can potentially have significant consequences on molecular signal transduction and other vital cellular functions, including ion pumps regulating electrolyte and water exchange (Chapin et al., 1999Go; Michelangeli et al., 1996Go). Zhang and O'Neil (1996) have reported the presence of an L-type calcium channel in renal epithelial cells. Chapin et al. (1999) have hypothesized an NP-induced ion pump defect as a potential mechanism of renal cyst formation. NP has also been reported to act via induction of oxidative stress (Okai et al., 2000Go) and as a genotoxin (Roy et al., 1997Go). It is plausible that NP or its metabolites may induce some renal tubular cysts through these estrogen receptor- and non-estrogen receptor-mediated potential mechanisms or others, but currently available data are insufficient for any conclusions to be drawn. The complex exposure regimen used in the present protocol, which involves indirect developmental exposure as well as direct dietary exposure of the pups, also does not allow conclusions to be drawn as to critical windows of exposure for the induction of renal cysts. Chapin et al. (1999) reported renal cysts only in generations that received NP developmentally, and not in the F0 generation that were exposed only as adults. Likewise, Cunny et al. (1997) did not report renal toxicity in a 90-day adult-only dietary exposure. We did not initiate the present experiment to address the issue of renal toxicity, and dams were not necropsied. However, the ongoing multigeneration experiment includes animals that are exposed only as adults as well as animals that are exposed only developmentally (i.e., in utero and preweaning), although the highest dose used is 750 ppm.

Comparing previous studies with this one (where the dose and route of exposure of NP are the same, but the diet is not), the striking difference in the severity of PKD observed leads to the conclusion that the renal toxicity of NP is highly dependent on the diet on which the animals are maintained. Furthermore, there appear to be some protective effects associated with soy-meal supplementation, although the dietary factors responsible are unknown. Considerable research is ongoing to test the endocrine-disruptor hypothesis that certain exogenous hormones (phytoestrogens) or hormone-active industrial pollutants may alter the development and function of the reproductive system in humans and animals. Recent studies have shown that the levels of phytoestrogens widely vary in diets used in experimental animal studies (Boettger-Tong et al., 1998Go; Thigpen et al., 1999aGo). As a result, some researchers advocate modifications of conventional diets to minimize the content of constituents known to have hormone action that could confound animal studies testing putative endocrine disruptors (Thigpen et al., 1999bGo). Although this is a rational approach, such alterations of the diet to eliminate exogenous "hormones" may have unanticipated consequences, such as the exacerbation of the renal toxicity of NP reported here. More research is needed to identify and characterize the specific dietary factors that modulate the susceptibility to renal cyst formation.


    ACKNOWLEDGMENTS
 
This work was supported by Interagency Agreement 224–93–0001 between the National Institute for Environmental Health Sciences and the United States Food and Drug Administration. We appreciate the considerable efforts of the experimental liaison and biostatistical support groups of ROW Sciences, the animal care and diet preparation staffs of Bionetics, the staff of Pathology Associates International, and the analytical group of Division of Chemistry at NCTR during the planning and conduct of this experiment.


    NOTES
 
1 To whom correspondence should be addressed at Pathology Associates International, P.O. Box 26, 3900 NCTR Road, Jefferson, AR 72079. Fax: (870) 543-7030. E-mail: jlatendresse{at}nctr.fda.gov. Back


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 DISCUSSION
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