Toxicological consequences of feeding PCB congeners to infant rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys

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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 μg 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).

Introduction

The toxicological effects of various commercial mixtures of polychlorinated biphenyls (PCBs) as well as individual PCB congeners have been studied in a myriad of species (Fishbein, 1974; Kimbrough, 1987; Kimbrough et al., 1978; McConnell, 1980, McConnell, 1985; Safe, 1984, Safe, 1994; Vos, 1972). We have previously conducted three pilot studies (Arnold et al., 1990; Truelove et al., 1982; Tryphonas et al., 1984, Tryphonas et al., 1986a, Tryphonas et al., 1986b) in an attempt to identify a non-human primate model for assessing the toxicological consequences of Aroclor® 1254 ingestion on reproduction (Arnold et al., 1993a, Arnold et al., 1993b, Arnold et al., 1995) using dosages that were comparable to the amount of PCBs that were assimilated or consumed by specific human subpopulations (Dillon et al., 1981; Kreiss, 1985; Lione, 1988). Aroclor 1254 was used to study the toxicological effects of PCBs since its chromatographic pattern was quite similar to the chromatographic pattern of PCBs found in human specimens (Kimbrough, 1987) and in various human foods (Kimbrough, 1987; Kolbye, 1983; Veith, 1975; Zitko et al., 1972). However, it was well known when our monkey studies were initiated that commercial mixtures of PCBs did not exist as such in nature, since some congeners were resistant to biodegradation and therefore became biomagnified in the food chain. Similarly, we have reported on which PCB congeners were accumulated in the blood of the dam, fat and breast milk following Aroclor 1254 ingestion as well as the congeners that were retained by the in utero and lactationally exposed infant (Mes et al., 1995a, Mes et al., 1995b, Mes et al., 1995c).

In an attempt to reduce the uncertainty when extrapolating toxicological data from one species to another, it was decided to modify our previous experimental model wherein we had fed rhesus dams Aroclor 1254 prior to mating, during gestation and through lactation (Arnold et al., 1993a, Arnold et al., 1993b). Consequently, the gestating and nursing infant monkey was exposed to the PCB congeners and metabolites of its dam's womb and breast milk. As we knew there were marked differences in the PCB congener composition of human breast milk and the breast milk of monkeys fed Aroclor 1254 (Mes and Marchand, 1987), we decided to separate the infant from its untreated dam at parturition and feed it a mixture of PCB congeners found in human breast milk. The selection of congeners for administration to the infants was tempered by reports describing quantitative and qualitative differences in the congener content of breast milk samples throughout the world (Bush et al., 1985; Dewailly et al., 1991; Dewailly et al., 1993; Duarte-Davidson et al., 1991; Gonzalez et al., 1994; Jensen, 1990; Johansen et al., 1993; Mes and Marchand, 1987; Newsome et al., 1995; Noren et al., 1990; Safe et al., 1985; Yakushiji et al., 1979). Differences in the PCB content of breast milk have been attributed to such factors as its fat content, maternal age, weight and parity; diet and dietary habits; as well as diurnal and seasonal variations (Jensen and Slorach, 1990). While there are reports that where one lives may affect the congener level in breast milk (i.e. urban and industrial areas greater than rural areas; Dewailly et al., 1991; Jensen, 1990), another group has not seen such differences (Duarte-Davidson et al., 1992). To enhance the Health Protection Branch's database concerning the PCB content of human breast milk (Morrison, 1978), it was decided to use a PCB congener mixture analogous to that in Canadian breast milk (Mes and Marchand, 1987). In addition to testing rhesus infant monkeys as we previously had, cynomolgus infants were also included in this experiment.

Section snippets

Material and Methods

A total of nine rhesus (Macaca mulatta: five males; minimum weight 400 g; four females; minimum weight 350 g) and 16 male cynomolgus (M. fascicularis; minimum weight 350 g) monkeys were procured from the Health Canada monkey breeding laboratory as soon as possible after parturition. The monkeys were randomly assigned to the control or treated group as follows: cynomolgus monkeys—six controls (animal numbers 6, 12, 15, 18, 21, 24) and 10 treated (an. nos 8, 10, 13, 14, 16, 17, 19, 20, 22, 23);

X-rays

Skeletal development was similar/normal for all infants

Formula consumption

There were no statistical differences between treated or control monkeys during the hand-reared, self-feeding or weaning from PRIMA-Lac consumption periods. However, the rhesus males did consume more formula during the self-feeding period than the females, which was supported by a significantly larger quadratic term during the self-feeding period (P=0.044).

Body weight

There were no statistically significant differences between the control and treated

Discussion

For the monitored parameters, there were few differences between the treated and the control group as a consequence of ingesting a mixture of PCB congeners simulating the congener mixture in Canadian breast milk. Some minor differences included the observation from the somatic data that the treated rhesus monkeys were bigger than the control infants, but this difference was not supported by increased formula or feed consumption, or in growth rate differences between the two groups. There was a

Acknowledgements

The authors would like to thank Ms W. Cherry, S. Fernie, F. Lacroix and E. MacLelland and Mr D. Davies for their technical assistance.

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