Chapter 12
Body Burden and Nonoccupational Exposure Assessment
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John A. Santolucito Harry Reid Center for Environmental Studies, University of Nevada, Las Vegas, NV 89154-4009
When assessing human exposures to pesticides or other toxicants, ambient monitoring is often supplemented with measurements of the toxicant's concentration in a tissue or body fluid in order to more accurately estimate exposure to internal targets. Tissue analysis is routinely carried out despite the uncertainty of the quantitative relationship between the amount of toxicant in a tissue and the intensity/duration of the human exposure. Classical toxicological studies, using experimental animals, do not substantially contribute to identifying and characterizing the uncertainties associated with human exposure assessments. There is a need to replace or supplement tissue burden determinations with measurements that will make more tangible contributions to quantitative exposure assessments. To fill this need, major emphasis is being placed on (1) the development of physiologically based pharmacokinetic models for simulating internal exposures, and (2) measuring, directly or indirectly, target tissue exposures. This paper examines the relationship of tissue or body burden to internal exposure for an organophosphate pesticide (EPN), a metal (Pb), and a volatile organic compound (benzene), and considers alternative approaches to more cost-effective exposure assessment in the general population.
The determination of a body burden to assess exposure of small organisms to environmental chemicals is a relatively straightforward task. Since the sample analyzed is the entire body, the amount of parent compound or metabolite present is the true body burden. For larger animals and humans, a true body burden can only be obtained by analyzing samples of each tissue/fluid compartment, estimating the mass of each tissue compartment, and summing the
0097-6156/94/0542-0178$06.00/0 © 1994 American Chemical Society
In Biomarkers of Human Exposure to Pesticides; Saleh, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
Downloaded by NORTH CAROLINA STATE UNIV on September 8, 2012 | http://pubs.acs.org Publication Date: November 23, 1993 | doi: 10.1021/bk-1992-0542.ch012
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Body Burden & Nonoccupational Exposure Assessment 179
derived tissue burdens. While this approach is feasible at autopsy, biological monitoring of living humans is usually restricted to tissues that can be sampled using noninvasive methods. The amount of toxicant present in less accessible tissues or in the whole body can theoretically be estimated from the amount present in the sampled tissue provided the pharmacokinetic and pharmacodynamic behavior of the toxicant and the approximate exposure scenario are known (1). In this approach, the tissue analyzed becomes a surrogate for the target tissue or whole body. In practice, attention is usually directed toward estimating a target tissue concentration rather than a body burden despite the uncertainty over which may be a better biomarker of exposure. Body burdens may reflect total exposure, as well as health risk, more accurately than a surrogate measure for bioaccumulating toxicants because both stored toxicant and that entering from ongoing exposure contribute to the target tissue dose. And in the event current exposure ceases, stored toxicant can impact target tissues until depleted. On the other hand, a surrogate measure may adequately assess current exposures to non-accumulating pollutants. Body Burden vs. Tissue Burden An attempt is made here to elucidate the relationships between body burden, tissue burden, and exposure by examining the results of published studies. Studies were targeted in which experimental animals were repeatedly or chronically exposed to toxicant and analyses performed on all or most of the major tissue compartments. Though these criteria were not fully met, the studies used contained data sets complete enough to reconstruct an approximate body burden. Together, the three studies presented address the organophosphate pesticide EPN and two widely dispersed environmental chemicals, lead (bioaccumulating) and benzene (non-bioaccumulating). Study 1: EPN (O-Ethyl O-4-Nitrophenylphosphonothioate). In a study reported by Abou-Donia et al. (2), hens weighing 1.5 kg were administered a single oral dose of 10 mg/kg of uniformly phenyl-labeled [ C] EPN (LD^) and sacrificed at 0.5, 2,4, 8, and 12 days after dosing. Tissue radioactivity (dpm/g, representing parent compound and metabolites combined) was reported for spinal cord, sciatic nerve, brain, lung, heart, RBC, plasma, liver, bile, kidney, muscle, adipose tissue, and skin. Though the data are not reproduced here, the highest concentration of C attained during the 12-day period was reported for liver followed by bile, kidney, adipose tissue, and muscle. Of the nervous tissues reported, brain contained the highest concentration of C, except on day 0.5 when sciatic nerve was highest, and spinal cord contained the lowest amount. The total body burden at day 12 was about 14% of the peak level seen at day 0.5. During the 12-day period of this study, approximately 90% of the measured body burden of EPN was contained in the liver, muscle, fat, and skin. For this exercise, the reported tissue radioactivities were multiplied by the estimated tissue weights to obtain tissue burdens. The percentages of body weight used to estimate each tissue weight for Callus gallus were: brain, 0.3; 14
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In Biomarkers of Human Exposure to Pesticides; Saleh, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
180
BIOMARKERS OF HUMAN EXPOSURE TO PESTICIDES
Downloaded by NORTH CAROLINA STATE UNIV on September 8, 2012 | http://pubs.acs.org Publication Date: November 23, 1993 | doi: 10.1021/bk-1992-0542.ch012
spinal cord, 0.3; peripheral nervous system, 0.01; lungs, 0.6; RBC, 3.1; plasma, 4.7; heart, 0.6; liver, 2.2; kidneys, 0.6; muscle, 45.0; fat, 5.0; skin, 5.0; feathers, 3.7; skeleton, 5.0; and GI tract, 20 (Bradley, personal communication, and 3-5). Relative tissue burdens, i.e., tissue burdens expressed as a percent of the body burden, are shown in Table I for each time interval. The radioactivity levels reported for sciatic nerve were considered representative of peripheral nerve tissue for this exercise and were used to estimate the tissue burden of the peripheral nervous system (PNS).
Table I. Tissue Burdens of EPN (Expressed as Percent of Body Burden) Days After Single Oral Dose of EPN Tissue
0.5
4
2
12
8
Relative Tissue Burden Brain
0.12
0.41
0.48
0.43
0.22
Sp. Cord
0.09
0.12
0.11
0.12
0.19
1
6.01
9.72
9.43
3.20
7.02
Lung
0.58
.73
0.57
0.20
.27
RBC
0.26
1.45
1.30
0.83
1.09
Plasma
0.63
2.87
2.88
0.53
0.33
Whole Blood
0.09
4.31
4.22
1.35
1.42
Heart
0.09
0.54
0.37
0.19
0.20
Liver
5.68
25.50
32.20
12.14
7.46
Kidneys
0.92
4.30
3.61
4.31
8.04
Muscle
80.72
49.96
43.97
59.52
63.67
Fat
6.24
8.82
9.01
13.49
8.89
Skin
4.67
5.29
5.50
8.24
9.65
Feathers
EPN content considered negligible
Skeleton
EPN content considered negligible
GI Tract
Tissue was not analyzed
PNS
1
xlO
5
In Biomarkers of Human Exposure to Pesticides; Saleh, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
Downloaded by NORTH CAROLINA STATE UNIV on September 8, 2012 | http://pubs.acs.org Publication Date: November 23, 1993 | doi: 10.1021/bk-1992-0542.ch012
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Body Burden & Nonoccupational Exposure Assessment 181
Relative tissue burdens for plasma, brain, liver, and fat decreased between days 8 and 12 and either increased or remained about the same for the remaining tissues (Table I). Thus, plasma E P N may be a satisfactory surrogate for brain, liver, and fat tissue burdens. However, of the nervous tissues analyzed, brain is the least susceptible to EPN-induced delayed neurotoxicity. Tissues with the least variable relative burdens of E P N over the 12-day observation period are those whose E P N burdens fluctuated in closest agreement with body burden and may be better surrogate markers of body burden than tissues with greater variability. Tissues in Table I with lowest coefficients of variation (CV) include: muscle, 24%; fat, 29%; spinal cord, 30%; skin, 32%; and PNS, 38%, none of which are readily available for routine monitoring. Admittedly, the short duration of the study is not representative of steady-state conditions seen with prolonged chronic exposure. Further, the extent to which the results obtained in this study, and the conclusions drawn from them, are applicable to humans is not known. Study 2; Lead. In this study, mice were administered a single intraperitoneal injection of 50 ng Pb, and the uptake in various tissues, as well as whole bodies, was plotted as a function of time. The data reported (6), were used to reconstruct the tissue burdens of lead shown in Table II. The mass of each tissue type, as percent of body weight, was obtained from compilations of morphological/anatomical measurements of laboratory mice (3,4,7). In addition to whole-body lead uptake, values were reported by Kumar for blood cells, plasma, liver, kidneys, pancreas, lungs, stomach, intestine, heart, thigh muscle, spleen, and femur (6). The lead content of tissues not analyzed was approximated as follows: the measured lead concentration of skeletal muscle was also used for abdominal fat based on a study of human accident fatalities showing these tissues to be among the lowest in lead concentration (8); the measured lead concentration of lung was applied to skin since both tissues are high in collagen; 150% of the measured lead concentration in mouse femur was applied to brain based on a study by F a n and Kennedy (9) showing the uptake of lead by rat brain to be about 50% higher than for bone one week after an injected dose; the measured lead concentration of the stomach was applied to the cecum because they are of similar composition; and for the same reason the measured lead concentration of spleen was applied to seminal glands, testes, and lymph nodes/thymus. The measured femur lead concentration was applied to the entire skeleton even though the literature confirms that lead concentration as well as lead kinetics varies between bones (10,11). Between 2 and 10 days post-injection, liver, erythrocyte, intestine, stomach, and cecum lead burdens decreased 70-80%; muscle, skin, kidney, pancreas, and lung decreased 50-60%; seminal gland, testis, lymphatic tissue, and spleen decreased 30-40%; abdominal fat, skeleton, and brain either remained the same or increased slightly. The plasma lead burden was very low at both 2 and 10 days post-injection. Examination of Table II shows good agreement between the lead body burden obtained by summing the individual tissue burdens (34.04 μg) and that 210
In Biomarkers of Human Exposure to Pesticides; Saleh, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
182
BIOMARKERS OF HUMAN EXPOSURE TO PESTICIDES
Table II. Reconstruction of lead body burden in mice % of B.W.
Downloaded by NORTH CAROLINA STATE UNIV on September 8, 2012 | http://pubs.acs.org Publication Date: November 23, 1993 | doi: 10.1021/bk-1992-0542.ch012
Tissue
Tissue Wt. (gm) 1
2
Percent of dose /gm of tissue (Tissue burden, /ig) 2 Days
10 Days
Skeletal Muscle
44.0
11.0
0.10 (0.55)
0.05 (0.28)
Skin
16.0
4.0
0.40 (0.80)
0.20 (0.40)
Abdominal Fat
10.0
2.5
0.10 (0.20)
0.05 (0.25)
Skeleton
8.2
2.1
22.00 (22.6)
23.00 (23.6)
Plasma
4.6
1.2
0.07 (0.04)
