Publications (48)129.85 Total impact

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    ABSTRACT: Toxaphene, which was added to glycerol/corn oil, was administered at a level of 1 mg/kg body weight/day in gelatin capsules to four healthy young adult cynomolgus (Macaca fascicularis) monkeys for 52 weeks. Four control monkeys ingested capsules containing only glycerol/corn oil. Each group had two males and two females. On a daily basis, each monkey's feed and water consumption was determined, its health was monitored and the females were swabbed to evaluate menstrual status. On a weekly basis, each monkey's body weight was determined and a detailed clinical evaluation was performed. At 4-week intervals, blood samples were taken for serum biochemistry, haematology and toxaphene analysis. Also, a local anaesthetic was administered to the nuchal fat pad area of each monkey, and adipose samples were obtained for toxaphene analysis. 1 day prior to the biopsies, a 24-h urine and faecal collection was obtained for toxaphene analysis. After 34 weeks of treatment, the immune system of the monkeys was evaluated. After 52 weeks of dosing, all treated and two control animals were necropsied. Liver samples were obtained and microsomal fractions were prepared immediately. A portion of liver and kidney was taken for toxaphene analysis. All of the major internal organs were weighed and bone marrow evaluations were conducted. Organ and tissue samples were fixed in 10% formalin and processed for light microscopy. There was no effect of treatment on body weight gain, feed consumption, water consumption or haematological parameters. Two major clinical findings were inflammation and/or enlargement of the tarsal gland and impacted diverticulae in the upper and lower eye lids. At necropsy, the relative spleen and thymus weights were greater for the treated monkeys than the controls. Toxaphene administration produced an increase in metabolism of aminopyrene, methoxyresorufin and ethoxyresorufin, three substrates that are altered specifically by cytochrome P450-based hepatic monooxygenase enzymes. Histopathological examination of tissues was unremarkable by light microscopy. Tissue analysis for toxaphene and immunology findings have been published elsewhere.
    Food and Chemical Toxicology 01/2002; 39(12):1243-51. DOI:10.1016/S0278-6915(01)00068-0 · 2.90 Impact Factor
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    ABSTRACT: Toxaphene, dissolved in glycerol/corn oil, was administered at 0.1, 0.4 or 0.8 mg/kg body weight/day in gelatin capsules to groups of 10 young adult female cynomolgus monkeys (Macaca fascicularis), while a group of five male monkeys (Macaca fascicularis) received 0.8 mg/kg body weight/day. Control male (a group of five) and female (a group of 10) monkeys ingested the glycerol/corn oil vehicle only. Treatment continued for 75 weeks. Testing for immune effects was initiated at 33 weeks of treatment. Immunization was initiated at 44 weeks of treatment. Pairwise comparisons between each of the treated female groups to the control indicated that the mean primary (post-immunization weeks 1-4) and secondary (post-immunization weeks 5-8) anti-SRBC IgM responses were significantly reduced at the 0.4 and 0.8 mg/kg body weight/day doses compared to the control (P< or =0.05). The mean primary (post-immunization weeks 1-4) anti-SRBC IgG response was significantly reduced compared to the control (P< or =0.05), while the secondary (post-immunization weeks 5-8) anti-SRBC IgG was not significantly affected by treatment (P>0.05). The mean anti-tetanus toxoid IgG response in the 0.8 mg/kg body weight/day dose group The mean primary anti-SRBC (IgM) response in the treated males was significantly different from the control (P<0.05), while the primary anti-SRBC IgG response was not affected by treatment. The mean absolute B-lymphocyte numbers in the female group administered 0.8 mg/kg of toxaphene was significantly reduced compared to the control (P< or =0.05). All other parameters including the natural killer cell activity, the delayed-type hypersensitivity response, the lymphoproliferative response of peripheral blood leukocytes to the mitogens Con A and PWM and the serum cortisol levels were not affected significantly by treatment (P>0.05). The no-observed-adverse-effect level (NOAEL) for the female monkeys based on the toxaphene effects on humoral immunity was 0.1 mg/kg body weight/day.
    Food and Chemical Toxicology 09/2001; 39(9):947-58. DOI:10.1016/S0278-6915(01)00035-7 · 2.90 Impact Factor
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    ABSTRACT: A total of 40 menstruating cynomolgus monkeys (Macaca fascicularis) with an average age of 7.25 +/- 1.06 years (standard deviation), five male cynomolgus monkeys with an average age of 12.6 +/- 0.66 years, and five male cynomolgus males with an average age of 6.2 +/- 0.23 years were obtained from the Health Canada breeding laboratory. The females were initially randomized to the four test groups in accordance with their previous reproductive success and body weight. They were then randomly allocated between two similar environmentally-controlled rooms (20 females/room). The males were randomly assigned to one of the test rooms (six or four males/room). The female test groups self-ingested capsules containing doses of 0, 0.1, 0.4 or 0.8 mg (Groups A, B, C, D) of technical grade toxaphene/kg body weight/day (i.e. five females/dose group/room). The older males (Group E) were proven breeders and were used exclusively for mating and their capsules contained no toxaphene. The younger males (Group F) ingested capsules containing 0.8 mg of technical grade toxaphene/kg body weight/day. After 20 weeks of daily dosing, it was assumed, based on the results of a pilot study [Andrews P., Headrick K., Pilon J.-C., Bryce F., Iverson F. (1996) Capillary GC-ECD and ECNI GCMS characterization of toxaphene residues in primate tissues during a feed study. Chemosphere 32, 1043-1053], that the treated monkeys had attained a qualitative pharmacokinetic steady state regarding the concentration of toxaphene in their adipose tissue and blood. On a daily basis, each monkey's feed and water consumption as well as its health were monitored. In addition, the females were swabbed daily to determine menstrual status. On a weekly basis, each monkey's body weight was determined and its dose of toxaphene adjusted. Detailed clinical examinations were conducted at intervals of 4 weeks or less. Periodically, starting prior to the initiation of dosing, blood samples were taken for serum biochemistry, haematology and toxaphene analysis. In addition, specimens from the nuchal fat pad were also obtained for toxaphene analysis. Statistical analysis did not reveal any effect of treatment on body weight gain, feed consumption, water consumption or haematological parameters during the 75-week pre-mating phase. The only serum biochemistry parameter which was consistently affected by treatment was cholesterol, the level of which decreased in a linear fashion as a consequence of dose, and this effect increased with time on test (P = 0.037). No other biological effects of toxaphene ingestion were found during the premating phase of this toxicological-reproduction study.
    Food and Chemical Toxicology 06/2001; 39(5):467-76. DOI:10.1016/S0278-6915(00)00151-4 · 2.90 Impact Factor
  • F Bryce · S Hayward · R Stapley · D L Arnold
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    ABSTRACT: A group of 80 female rhesus (Macaca mulatta) monkeys were randomly distributed to four similar test rooms (20 monkeys/room) and then randomly allocated to one of five test groups (four females/test group/room). The objective of the study was to ascertain the toxicological and reproductive effects of Aroclor 1254 ingestion at dose levels of 0, 5, 20, 40 or 80 microg Aroclor 1254/kg body weight per day (Arnold et al., 1993a,b, 1995, 1996, 1997). It was deemed necessary to establish the menstrual patterns for all the monkeys both before and after the start of dosing so as to provide an appropriate baseline from which potential treatment effects could be ascertained. The data presented herein were obtained during the first 3 years after the start of dosing, or the study's pre-mating phase. At the end of the first 2 years of dosing, the monkeys attained a qualitative pharmacokinetic steady state regarding the levels of polychlorinated biphenyls in their adipose tissue. Upon termination of the study, a number of monkeys were found to have endometriosis, adenomyosis or uterine leiomyomas (Arnold et al., 1996, 1997). These monkeys were designated as having gynecological abnormalities which were considered to be a factor in the analysis of the menstrual data. The menstrual data (i.e. menses frequency, cycle length and menses duration) were subjected to a statistical assessment to see whether year, quarter, gynecological abnormalities or dose of Aroclor 1254 had any effect on menses frequency, menstrual cycle length (i.e. the first day of menses until the day prior to the start of the next menses) and/or menses duration (i.e. the number of days of haemorrhagic discharge). The only consistent statistically significant effect found was that gynecological abnormalities increased menses duration (P<0.05) in all 12 quarters of the premating observation period. This effect was significant during both the pre- (P=0.0004) and post- (P< or =0.0001) pharmacokinetic steady-state intervals. While there was some indication of seasonality regarding menstrual cycle length and menses duration when these data were compared on a quarterly basis during the first 2 years of the study (P=0.043; P< or =0.0001, respectively), this effect was not evident during the third year (P=0.21; P=0.31, respectively). In particular, the effect of quarter on menses cycle length was most evident during the first year, with the shortest cycles occurring during the first or spring quarter and the longest in the third or fall quarter. However, menses duration was shortest in the first quarter during the first 2 years and tended to peak in the second quarter of all 3 years, while generally diminishing in the third and fourth quarters. There was also an increase in menses duration with increasing time on test for all groups. In addition, Aroclor 1254 treatment appeared to have some effect on menses duration when menses duration was plotted against dose group, but the effect was not statistically significant (P>0. 05). It was concluded that the ingestion of Aroclor 1254 at dose levels up to 80 microg/kg body weight/day by rhesus monkeys did not have any appreciable biological effect on menstrual frequency, menstrual cycle length or menses duration. However, gynecological abnormalities significantly increased menses duration during the three-year observation period.
    Food and Chemical Toxicology 11/2000; 38(11):1053-64. DOI:10.1016/S0278-6915(00)00094-6 · 2.90 Impact Factor
  • D L Arnold · F R Bryce · D J Clegg · W Cherry · J R Tanner · S Hayward
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    ABSTRACT: The choice of a dosing route for in vivo toxicological tests is often dictated by practical constraints. Reproduction studies are particularly challenging in this regard since the determination of no-effect levels and allowable daily intakes from reproduction data encompasses exposure of the dam to the test xenobiotic prior to pregnancy, during gestation and during lactation. The fetus/infant can be exposed to the xenobiotic as well as the dam's metabolic products of the test xenobiotic during gestation and lactation. We initiated a series of two-litter, pilot reproduction studies with Sprague-Dawley and Fischer 344 rats to specifically ascertain the amount of xenobiotic and its metabolites ingested by the nursing neonate on lactation days 4, 7, 12, 17 and 21, when its dam received the xenobiotic via its diet or by gavage. The xenobiotics studied in this initial series of experiments were hexachlorobenzene (HCB) and Aroclor(R) 1254 (polychlorinated biphenyls; PCBs). The dams were dosed for 28 days, mated to untreated males and then remated approximately 2 weeks after weaning their first litter to a second untreated male. Dietary levels of 10 ppm HCB or 10 ppm PCBs, and gavage doses of 0.9 mg HCB or 0.8 mg PCBs/kg body weight/day were chosen and resulted in similar doses of HCB and PCBs per unit of the body weight of the dam during the premating period. There were no apparent toxicological effects regarding the dam nor were any of the reproduction parameters (feed consumption, dam weight, litter size, pup weight, external anomalies and day 4 viability index) significantly different from control values. Following impregnation, the body weight of the dam increased appreciably during gestation, but its feed consumption increased only slightly. During lactation, the dam's feed consumption increased markedly while its body weight increased slightly. Consequently, when dams received the xenobiotic in their diet they consumed slightly less xenobiotic per unit of body weight during gestation when compared to the gavaged dams, whereas the situation was dramatically reversed during lactation. While the greater consumption of xenobiotic by the dietary-dosed dams during lactation did result in more HCB (P</=0.0001 for both litters) and PCBs/metabolites (litter one: P=0.05; litter two: P</=0.0001) in the suckling neonate's stomach contents in both generations, there was no evidence of any differences between the two litters when each sampling date was assessed separately, except for the day 4-HCB results when the litter one pups had more HCB in their stomachs (P=0.018). For the PCBs, the F344 neonates were found to have more PCBs in their stomachs (litter one P=0.0015; litter two P=0.002) than the Sprague-Dawley neonates. In addition, the amount of HCB, PCBs and fat in the neonates' stomachs decreased during lactation, as the pups age increased (P</=0.035). These preliminary results suggest that analogous amounts of HCB and PCBs given via diet or gavage may not result in similar lactational exposure by the suckling neonate.
    Food and Chemical Toxicology 09/2000; 38(8):697-706. DOI:10.1016/S0278-6915(00)00060-0 · 2.90 Impact Factor
  • D L Arnold · F Bryce · J Mes · H Tryphonas · S Hayward · S Malcolm
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    ABSTRACT: In a study designed to minimize interspecies extrapolation of toxicological data, nine rhesus (Macaca mulatta) and 15 cynomolgus (M. fascicularis) day-old infant monkeys were separated from their dams following parturition and hand-reared using a liquid non-human primate formulation. The infants were randomly divided into a control and a treated group which received a mixture of polychlorinated biphenyl (PCB) congeners analogous to those found in breast milk from Canadian women. The concentration of congeners in the dosing media resulted in each infant receiving a total of 7.5 microg PCB congeners/kg body weight/day. The congeners were added either to the liquid formulation or to corn oil and administered to the back of the monkey's mouth for 20 weeks. Monthly blood and adipose specimens were obtained during the dosing period and then periodically until the monkey was necropsied or taken off test (minimum of 66 weeks on test) for congener analysis. Parameters such as body weight, formula consumption, tooth eruption, somatic measurements, haematology and serum biochemistry were monitored throughout the study. In addition, a qualitative evaluation of the absorption and depletion of the various congeners was undertaken as was an immunological evaluation. For the monitored parameters, very few differences were found to be statistically significant. For the immunological parameters, the only statistically differences found were a reduction over time for immunoglobulins M and G antibodies to sheep red blood cells (cyno, P = 0.025; rhesus, P = 0.002) and a treatment-related reduction in the levels of the HLA-DR cell surface marker (mean percent, P = 0.016; absolute levels, P = 0.027). There were some qualitative differences regarding absorption and depletion rates for the various congeners, but it could not be definitely ascertained whether these differences were due to species differences or dosing mode. However, statistically significant differences were found for treatment (P = 0.0293) as well as for species and vehicle regarding the concentration of PCB in blood (species;--P = 0.0399; treatment--P = 0.0001) and adipose tissue (species--P = 0.0489; treatment--P = 0.0001).
    Food and Chemical Toxicology 02/1999; 37(2-3):153-67. DOI:10.1016/S0278-6915(98)00120-3 · 2.90 Impact Factor
  • D L Arnold · P F McGuire · D Miller · S Malcolm · S Hayward · A Paquet
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    ABSTRACT: Two experiments with Sprague Dawley rats tested their ability to hydrolyse myristoyl-methionine (M-M) into myristic acid and L-methionine (M). In the first experiment, lasting for 3 days. male rats were orally administered [9,10-3H]myristoyl-L-[35S]methionine. The recovery of radioactivity was approximately 90% for both isotopes; 19% of the administered 3H was recovered in the urine and 16% in the faeces, while the recovered 35S activity was 13 and 12%, respectively. The balance of the radioactivity was found among the tissues, organs and blood. In the second experiment, male and female rats received soybean-based diets which were supplemented with either 0.305% M-M or 0.2% M (both diets contained equal amounts of M) for periods up to 4 weeks. The growth rate of the rats receiving the 0.305% M-M diets was slightly slower than that for the rats on the 0.2% M diet, but the difference was not statistically significant (P > 0.05). The M-M rats had a transitory decrease in feed consumption, suggesting that palatability may have contributed to the growth difference and that a somewhat greater amount of M-M was necessary for the rat to attain the same growth rate as that produced by 0.2% M. When the amount of dietary M-M was increased to 3.05% M-M, a greater reduction in feed consumption and body weight gain was observed. This latter diet was an initial attempt to study the potential toxicity of M-M. None of the haematological, clinical chemistry or organ weight data suggested that M-M was overtly toxic per se, but longer-term feeding studies are needed to evaluate the potential toxicity of M-M more fully.
    Food and Chemical Toxicology 09/1998; 36(9-10):771-9. DOI:10.1016/S0278-6915(98)00044-1 · 2.90 Impact Factor
  • D L Arnold · R Stapley · F Bryce · D Mahon
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    ABSTRACT: Fish from the Great Lakes can be contaminated with a plethora of industrial, agricultural, and environmental chemicals. These chemicals have been associated with reproductive and other toxicological effects in fish and fish-eating birds found in the Great Lakes basin. To obtain more insight into this association, several laboratory studies have been undertaken wherein fish have been incorporated into the experimental diets to determine the effect of their ingestion upon the test animals. In addition, several human epidemiological studies have found correlations between Great Lakes fish consumption and effects in neonates which have been attributed to polychlorinated biphenyls without any appreciable consideration as to what synergistic or antagonistic effects other chemicals or heavy metals may or may not have contributed to the observed findings. Herein is presented the design of a two-generation feeding-reproduction study that incorporated lyophilized chinook salmon (Oncorhynchus tsawytscha) fillets into the diets of Sprague-Dawley rats. The findings of this study will be presented in the sections which follow.
    Regulatory Toxicology and Pharmacology 03/1998; 27(1 Pt 2):S1-7. DOI:10.1006/rtph.1997.1186 · 2.14 Impact Factor
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    ABSTRACT: The effects of Great Lakes fish contaminants on several quantitative and functional aspects of the immune system were investigated in the first (F1) and second (F2) generations of Sprague-Dawley rats. The F0 rats were fed either a control diet or diets containing 5 or 20% lyophilized chinook salmon from the Credit River of Lake Ontario (LO) and Owen Sound point of Lake Huron (LH). The F1 and F2 pups were exposed to fish in utero, through the dam's milk to 21 days old, and through the dam's respective diets to 13 weeks of age. The study included an F1-reversibility (F1-R) phase in which rats at 13 weeks of exposure to fish or control diets were switched to the control diet for 3 months. The most outstanding finding was a statistically significant increase in absolute spleen leukocytes and absolute and percentage lymphocytes in the F2 male rats fed the LH fish diets compared to the control and to those fed the LO fish diets with the 20% fish diets having higher cell numbers compared to the LO-5% fish diets. A parallel increase in the T-helper/inducer T-lymphocyte subset numbers was observed. Increased but statistically insignificant plaque-forming cell (PFC) numbers were obtained in the F2 male rats fed the LH fish diets compared to those fed the LO fish diets and in the F1-R female group of rats fed the LH fish diet compared to those fed the LO fish diets. Phagocytosis by resident peritoneal macrophages was significantly increased in the F1 male and F2 female rats fed the fish diets compared to the control. The phagocytic activity was significantly higher in the F2-generation male and female rats fed the LO diets compared to those fed the LH diets. Other parameters including lymphocyte transformation in response to mitogens, the number of Listeria monocytogenes bacteria surviving in the rat spleens, and the natural killer cell activity were not affected significantly by any of the treatments. Overall, the effects of diets containing chinook salmon from the LO and LH sources on the immune system of rats were minimal and were on quantitative rather than on functional aspects of the system. Further focused research would be required in order to establish conclusively that the immune system of cohorts who ingest Great Lakes fish frequently is at a greater risk for adverse effects.
    Regulatory Toxicology and Pharmacology 03/1998; 27(1 Pt 2):S40-54. DOI:10.1006/rtph.1997.1190 · 2.14 Impact Factor
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    ABSTRACT: A two-generation reproduction-feeding study was undertaken with Sprague-Dawley rats to ascertain the effects of ingesting chinook salmon fillets caught in the Credit River, which empties into Lake Ontario (LO), or in the Owen Sound region of Lake Huron (LH). Rats (30/sex/group) were randomly assigned to groups whose dietary protein consisted of casein and/or lyophilized salmon [Group 1: 20% casein (controls); Group 2: 15% casein + 5% LO salmon (LO-5%); Group 3: 20% LO salmon (LO-20%); Group 4: 15% casein + 5% LH salmon (LH-5%); Group 5: 20% LH salmon (LH-20%)]. After 70 days on test, the males and females were mated on a 1:1 basis within diet groups. Approximately 70 days postweaning, one F1 male and one F1 female from 24 litters were mated within diet groups, avoiding sibling matings. At weaning, the F0 and F1 adults and the F1 and F2 neonates not randomly selected for further testing were necropsied. Evaluated parameters included growth, feed consumption, organ weights, reproduction indices, serum chemistry, hematology, and coagulation times. The only statistically significant effects which were present in both generations were increased relative liver and kidney weights of both sexes in the LO-20% and LH-20% groups; the LH-20% females had lower alanine transaminase activity than the controls; the controls had lower creatinine levels than the fish groups and the LO-20% females; the LH-20% and LO-20% males had a lower blood urea nitrogen than the controls; and the LH-20% females had a heavier terminal body weight than the controls and a lower number of red blood cells, hematocrit, hemoglobin values, and mean platelet volume. There was a tendency for the fish-fed groups to grow faster, eat more feed, and have larger litters with heavier pups. Overall, there was little to suggest that the myriad of contaminants in chinook salmon from the Great Lakes presented an appreciable toxicological risk to Sprague-Dawley growth and reproduction.
    Regulatory Toxicology and Pharmacology 03/1998; 27(1 Pt 2):S18-27. DOI:10.1006/rtph.1997.1188 · 2.14 Impact Factor
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    ABSTRACT: The effects of Great Lakes fish on food consumption, body and organ weights, and hematological parameters were investigated in the first- (F1) and second- (F2) generation Sprague–Dawley rats assigned to immunological studies. The parent- (F0) generation rats were fed either a control diet or diets containing 5 or 20% lyophilized chinook salmon from Credit River (Lake Ontario, LO) or Owen Sound (Lake Huron, LH). The F1and F2pups were exposed to the fish dietin utero,through the dam's milk to 21 days of age and through the respective diets to 13 weeks of age. The study included an F1-reversibility (F1-R) phase in which rats at 13 weeks of exposure to fish or control diets were switched to the control diet for 3 months. Statistically significant effects included increased growth rates in the F1male rats fed the LH fish diets compared to those fed the LO fish diets; increased liver weights in the F2-generation male rats fed the LH-20% and LO-20% diets compared to those fed the 5% fish diets; reduced thymus weights in the F1-R female rats fed the LO-20% fish diet compared to those fed the LO-5% or LH-20% fish diets and in the F2male rats fed the LO diets compared to those fed the LH diets; increased kidney weights in the F2male rats fed the LH-20% diet compared to those fed the LH-5% or LO-20% diets; reduced but reversible effects on red blood cell (RBC), white blood cell (WBC), neutrophil, lymphocyte, and monocyte numbers in the F1-generation female rats fed the fish diets; reduced red blood cell (RBC), white blood cell (WBC), and lymphocyte numbers in the F2male rats fed the LO diets compared to those fed the LH diets; and reduced WBC and lymphocyte numbers in the F2female rats fed the LO-20% diet compared to those fed the LH-20% fish diet. These results suggested that long-term exposure to Great Lakes fish contaminants may have adverse effects on some immune-related parameters. The impact of such changes on the functional aspects of the immune system of rats and consequently on human health needs to be further investigated.
    Regulatory Toxicology and Pharmacology 02/1998; 27(1):S28–S39. DOI:10.1006/rtph.1997.1189 · 2.14 Impact Factor
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    ABSTRACT: A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar rooms (20 monkeys/room) and then to one of five dose groups (four females/dose group/room). Each day the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 microg Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their nuchal fat pad. Concurrently, sebaceous glands were being examined for changes analogous to chloracne. Subsequently, the females were paired with untreated males. The infants' blood PCB levels at birth were not correlated with its dam's dose or blood PCB level. However, there was an association between an infants preweaning blood PCB levels and its dam's dose and PCB milk levels. After weaning, the infants were not dosed with PCB. The half-life for the PCB in the infants' blood was determined and found to be slightly more than 15 wk. After 6 yr on test, three monkeys from the 0, 5, 20 and 40 microg dose groups were randomly allocated to a depletion study to ascertain the half-lives of specific PCB congeners (Mes et al., Chemosphere 1995, 30, 789-800). Concurrently, necropsies began of the remaining females, and of seven infants from the treated dams and four infants from the control dams, which had attained an age of 2 yr. Approximately 3 yr later, the depletion monkeys were necropsied. The only statistically significant treatment-related pathological changes found during the study were in the adult females, in which an involution of the sebaceous glands and a dose related increase in liver weight due to hyperplasia were evident.
    Food and Chemical Toxicology 01/1998; 35(12):1191-207. DOI:10.1016/S0278-6915(97)85470-1 · 2.90 Impact Factor
  • D.L. Arnold · S. Hayward
    Food and Chemical Toxicology 01/1998; 36(5). DOI:10.1016/S0278-6915(98)00027-1 · 2.90 Impact Factor
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    D L Arnold · E A Nera · R Stapley · G Tolnai · P Claman · S Hayward · H Tryphonas · F Bryce
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    ABSTRACT: A total of 80 menstruating rhesus monkeys (Macaca mulatta) were equally and randomly divided among groups receiving 0, 5, 20, 40, or 80 mu g of Aroclor 1254/kg body weight/day during a 6-year toxicological-reproduction study. During the first 3 years of the study, 4 of the treated monkeys became moribund and were euthanized; 3 had endometriosis. This finding suggested a possible link between the PCB treatment and the occurrence of endometriosis. However, neither a laparoscopic examination of the control and high-dose monkeys nor the necropsy data provided evidence for a possible link between the PCB treatment and the observed incidence (37% (6/16) of controls; 25% (16/64) of treated monkeys and/or the severity of the endometrial lesions. Additional clinical and historical data not contained in previous reports are presented to facilitate independent evaluation of the relationship between PCB ingestion and endometriosis. We conclude that the incidence and severity of the endometriosis lesions observed in the rhesus monkeys utilized in this study did not have any relationship with the dosages of Aroclor 1254 they ingested.
    Fundamental and Applied Toxicology 06/1996; 31(1):42-55.
  • J Mes · D L Arnold · F Bryce
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    ABSTRACT: Polychlorinated biphenyl (PCBs) analyses were made on prenecropsy blood samples and postmortem adipose, liver, kidney, and brain tissues from female rhesus monkeys fed a daily dose of 0, 5, 20, 40, or 80 micrograms Aroclor 1254/kg body weight for approximately 6 years. During this time, the females were bred with non-dosed males. All resulting offspring were nursed for 22 weeks and fed no additional PCBs until they were necropsied at approximately 120 weeks after birth. PCBs were also measured in necropsied infant tissues to determine PCB levels due to intake of PCB-contaminated milk from the dosed dams, in addition to in utero exposure. Polychlorinated biphenyl levels in all tissues of the adult monkeys increased with their dosage. The highest PCB levels were found in adipose tissue and the lowest levels were found in the brain. Polychlorinated biphenyl residues in the cortex of the kidney were lower than in the medulla, while in the brain no appreciable differences were observed between the occipital and frontal lobes. Necropsy tissues of infants from dosed dams contained more PCBs than those nursed by controls, but less than tissues from stillborn infants. Although no differences were observed between PCB tissue levels from monkeys having offspring and those having no offspring, those having a stillborn infant had higher PCB levels in their tissues than those with a viable infant. Similarly, monkeys that were euthanized because of poor health had higher PCB levels in their tissues than those necropsied at the conclusion of the study and showed a dramatic shift from tetra- and hexachlorobiphenyls to penta- and heptachlorobiphenyls in their tissues. The PCB distribution pattern in tissues from a dosed mother/infant pair differed considerably. A larger percentage of heptachlorobiphenyls was found in the infant than in its dam. The adipose/blood PCB ratio in the adult monkeys remained remarkably constant.
    Archives of Environmental Contamination and Toxicology 08/1995; 29(1):69-76. DOI:10.1007/BF00213089 · 1.96 Impact Factor
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    Jos Mes · Douglas L. Arnold · Fred Bryce
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    ABSTRACT: Specific polychlorinated biphenyl (PCB) congeners were measured before, during, and after gestation in the blood of rhesus monkeys, as well as in their milk and in the blood of their infants during lactation, as part of a long-term feeding study to evaluate the toxicology of Aroclor 1254 on pre- and postnatal development of infant monkeys. During gestation a considerable shift from the higher to lower chlorinated biphenyls in the blood was observed in both dosed and nondosed animals. The contribution of penta- and hexachlorobiphenyls in the milk slightly increased with higher dosage. In addition, the percentages of 2,2'3,4,5'-,2,2',4,5,5'-, and 2,3,3',4',6-pentachlorobiphenyls were remarkably lower in the milk of dosed dams than in the originally ingested Aroclor 1254. PCB congener levels in infant blood increased during the lactation period but immediately decreased upon weaning. The lower chlorinated biphenyls virtually disappeared from infant blood after 16 weeks of nursing. Some correlations were observed between PCB congener levels in mother and infant and the congener ratios calculated.
    Journal of analytical toxicology 07/1995; 19(4):209-17. DOI:10.1093/jat/19.4.209 · 2.63 Impact Factor
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    ABSTRACT: A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar test rooms (20 monkeys/room) and then randomly allocated within each room to one of five dose groups (four females/dose group/room). Each day, the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their adipose tissue. Commencing on test month 37, each female was paired with an untreated male until either an impregnation occurred or the 29-month breeding phase of the study was completed. The females continued to receive their daily test dose during mating and gestation. To preclude an infant ingesting the mother's dosing capsule, dosing of the dam was discontinued when a nursing infant was approximately 7 wk old. Treatment was restarted when the infant was weaned at 22 wk of age. At parturition, and every 4 wk until weaning, milk and blood samples were obtained from the dam and a blood sample was obtained from the infant for PCB analysis. When the infant was 20 wk old, immunological testing was initiated and an adipose sample was obtained from the infant and dam for PCB analysis. Subsequently, further adipose and blood samples were obtained from the infant and blood specimens were obtained from the dam for PCB analysis. Concurrently, each infant was subjected to anthropometric measurements and detailed clinical examinations until it was approximately 122 wk old. At 122 wk some of the control and all of the treated infants were killed humanely and autopsied. A statistical analysis of the reproduction data provided evidence for a significant decreasing dose-related trend in conception rates and a significant increasing dose-related trend in foetal mortality. Several comparisons between impregnated and non-impregnated females did not implicate 'age' as a confounding factor regarding these results. The major findings with the infants involved some immunological test differences and mild clinical manifestations of PCB ingestion.
    Food and Chemical Toxicology 07/1995; 33(6):457-74. DOI:10.1016/0278-6915(95)00018-W · 2.90 Impact Factor
  • Jos Mes · Douglas L. Arnold · Fred Bryce
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    ABSTRACT: The levels of thirty polychlorinated biphenyl congeners in the blood of female rhesus monkeys, previously dosed with Aroclor 1254 for over six years, were monitored every two weeks during the first year and monthly during the subsequent two years after dosing was discontinued. Both blood lipid and polychlorinated biphenyl congener levels generally declined during this post dosing period. The percent distribution of the PCB congeners during the post dosing period remained relatively constant with more than half of all polychlorinated biphenyls consisting of the mono-orthochlorine substituted biphenyls. The contribution of the mono-orthochlorine substituted biphenyls was significantly different for one out of three monkeys in two of the three dose groups, during the post dosing period. Half-life, estimations for nine of the congeners ranged from 0.3-7.6 years.
    Chemosphere 03/1995; 30(4):789-800. DOI:10.1016/0045-6535(94)00408-M · 3.50 Impact Factor
  • S Fernie · E Wrenshall · S Malcolm · F Bryce · D L Arnold
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    ABSTRACT: During the conduct of a long-term toxicity/reproduction study using rhesus monkeys (Macaca mulatta), periodic hematologic and serum biochemical analyses were undertaken on blood obtained from 15 untreated (vehicle control) adult female monkeys over a period of 3 yr, 20 untreated adult males over a period of 6 yr, and 9 infants (5 male, 4 female, whose dams were the vehicle control females) from 12 wk through 2 yr of age. All samples were obtained by femoral puncture. To facilitate handling, ketamine hydrochloride (Ket.HCl) was administered to the males, and for some of the later infant samplings. Complete blood cell counts were performed using electronic cell counters, while reticulocyte counts and leukocyte differentials were assessed manually. The serum biochemistry analyses were performed with automated analyzers. These data were obtained as part of a health monitoring program, with medians and 2.5 to 97.5 percentiles for each parameter indicated. Some monitored parameters were found to be affected by the type of equipment used and by the use of Ket.HCl.
    Journal of Toxicology and Environmental Health 06/1994; 42(1):53-72. DOI:10.1080/15287399409531863 · 1.81 Impact Factor
  • J Mes · D L Arnold · F Bryce
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    ABSTRACT: Analytical and quality control procedures are described for the determination of polychlorinated biphenyls in blood, adipose tissue, and milk from dosed female monkeys and their offspring, as part of a study to measure the toxicological effect of Aroclor 1254 on the pre- and postnatal development of fetus and infant, respectively. Recoveries of polychlorinated biphenyls from fortified blood, fat, and milk of monkeys ranged from 81 to 96%, whereas recoveries from fortified corn oil, used to evaluate routine analysis, ranged from 94 to 108%. The coefficient of variation for triplicate analyses of lipids and polychlorinated biphenyls in blood or adipose tissue or both was less than 10%. Polychlorinated biphenyl levels in blood, milk, and fat rose with increasing dosage. After weaning, when the infants were no longer exposed to polychlorinated biphenyls, their blood levels declined rapidly and approached maternal levels within 40-50 weeks. Approximately 100 weeks after weaning, polychlorinated biphenyl levels in adipose tissue of infants from treated dams reached the background levels of those in the control group.
    Journal of analytical toxicology 01/1994; 18(1):29-35. DOI:10.1093/jat/18.1.29 · 2.63 Impact Factor