Pharmacokinetics of methylmercury in the blood of monkeys (Macaca fascicularis)

FUNDAMENTAL AND APPLIED TOXICOLOGY 12,23-33 (1989)

Pharmacokinetics of Methylmercury in the Blood of Monkeys (A4acaca fascicularis) DEBORAH Food Directorate,

C. RICE,’ DANIEL Health

Protection

Received

KREWSKI,~ Branch,

September

Health

B. T. COLLINS,~ AND ROBERT F. WILLES~ & Welfare

25.1987:

Canada,

acceptedJune

Ottawa,

Ontario,

Canada

KlA

OL2

13, I988

Pharmacokinetics of Methylmercury in the Blood of Monkeys (Macaca fascicularis). RICE, D. C., KREWSKI, D., COLLINS, B. T., AND WILLES, R. F. (1989). Fundam. Appl. Toxicol. 12, 23-33. Statistical analysis of the blood mercury profiles of groups of two and four adult female cynomolgus monkeys (Macacafascicularis) given single oral doses of 500 pg and 50 &i (25.3 pg) methylmercury/kg body wt, respectively, indicates that a two-compartment model best describes the absorption and elimination of methylmercury in blood. Absorption was largely complete within 6 hr, and the half-time of methylmercury during the terminal elimination phase ranged from 10 to 15 days. In addition, three groups of five adult female cynomolgus monkeys were dosed with methylmercury every Monday, Wednesday, and Friday for periods up to 2 years at effective doses of 10,25, or 50 pg methylmercury/kg body wt/day. The average blood levels at steady state were estimated to be 0.27 it_ 0.02, 0.69 f 0.03, and 1.51 * 0.08 ppm, respectively, with average time taken to achieve 95% of the steady-state blood level being about 92 days. The steady-state blood levels obtained via extrapolation of the results from the two single-dose experiments were significantly different from those actually achieved, indicating that the average steady-state blood levels under chronic dosing conditions may not be accurately estimated on the basis of short-term experiments. The data were also used to examine the impact of different dosing intervals on variation in blood mercury levels. o 1989SchtyofTodcdogy.

Methylmercury represents a significant risk to human health when present in excessive amounts in the food chain (WHO, 1976). Methylmercury is absorbed readily from the gastrointestinal tract and distributes to all parts of the body (Friberg and Vostal, 1972; WHO, 1976). It accumulates in significant amounts in the body due to its long half-time of elimination. Tracer studies with hu-

mans estimate the half-time in red blood cells at around 50 days (Miettinen et al., 197 1). Methylmercury ingested into humans through fish or contaminated food at doses estimated between 5 and 50 @g/kg/day has a biological half-time in blood between 33 and 189 days (Birke et al., 1972; Skerfving, 1974; Bakir et al., 1973). There is evidence for a bimodal distribution for elimination of methylmercury, with part of the population showing a mean whole-body half-time of 65 days, and a smaller segment of the population with much longer half-times (Al-Shahristani and Shihab, 1974). There has been a substantial amount of research on the effects of methylmercury poisoning utilizing primate models (Willes et al., 1978; Burbacher et al., 1984; Gunderson et al., 1986; Lok, 1983; Chen et al., 1983; Kato

’ To whom correspondence should be sent. * Present address: Environmental Health Directorate, Health Protection Branch, Health & Welfare Canada, Ottawa, Ontario, Canada K 1A OL2. 3 Present address: Biometrics Division, Environment Canada, Place Vincent Massey, Hull, Quebec, Canada KlA OE7. 4 Present address: HMW & Assoc. Ltd., Health & Safety Consultants, P.O. Box 6696, Station “I”, Ottawa, Ontario, Canada K2A 3Y7. 23

0272-0590/89$3.00 Copyrisht0 1989 by the AU rights of reproduction

Society of Toxicology. in any fom reserved.

24

RICE ET AL.

et al., 198 1; Sato and Ikuta, 1977; Luschei et al., 1977; Kawasaki et al., 1986; Berlin et al., 1975a,b; Evans et al., 1975, 1977; Merigan, 1980; Merigan et al., 1983; Finocchio et al., 1980; Rice and Gilbert, 1982; Garman et al., 1975; Shaw et al., 1975, 1979; Hellberg and Nystrom, 1972). A variety of doses and dosing regimens have been used by these and other investigators in attempts to characterize methylmercury toxicity. The kinetics of methylmercury in the monkey must be understood as well as possible to extrapolate findings from the monkey to humans. In addition, the effect of dosage regimen, specifically the choice of dosing intervals on the kinetics of methylmercury and therefore on its biological effect, requires careful consideration to correlate clinical, behavioral, and pathological effects in animals with effects in humans. This paper explores the kinetics of methylmercury in the blood compartment of a macaque species (Macacafascicularis). The purpose of this investigation was threefold: (1) to determine the pharmacokinetics (i.e., absorption and elimination) of methylmercury in the blood of monkeys, (2) to evaluate how well estimates from acute exposure studies predict results obtained under conditions of chronic exposure, and (3) to investigate theoretically the consequences of different dosing regimens on variation in blood mercury levels under chronic dosing conditions. METHODS Experimental Procedures Single dosing. Two adult female cynomolgus monkeys (Macaca fascicularis) were gavaged with 500 j&kg mercury as methylmercuric chloride after I2 hr of food and water deprivation (Experiment I). Blood was collected by femoral puncture at 0, 1,2, 3,4, 5,6, 12, and 24 hr, and 2, 3, 4, 7, 14, 21, 28, 35, 42, 49, and 56 days following dosing, and analyzed for total mercury by atomic absorption spectrophotometry (Iverson et al., 1974). Four juvenile (3- to 4-year-old) female cynomolgus monkeys were gavaged with 50 &i (25.3 pg) mercury as methylmercutic chloride per kilogram kg body weight (Experiment II).

Radioactive methylmercuric chloride (specific activity I .98 mCi/mg Hg) was received in solution from New England Nuclear (Boston, MA). The dosing solution was prepared by adding the stock solution containing 5 mCi to 50 ml of 0.05 M Na2C03 to give 100 &i/ml. Each monkey was gavaged with 1.5-2.0 ml of dosing solution, depending on body weight. Ten milliliters of vehicle NaZC03 solution was then flushed through the gavage tube into the monkey’s stomach. Blood was sampled by femoral venipuncture at 0.5, 1,2,4,6, 14,2 1,28,35,42, 49, 56, 63, 78, 92, and 120 days. Blood mercury levels were measured with a Beckman Gamma-2 counter using the standard window settings as quoted by the manufacturer. A standard counting solution was prepared by diluting the dosing solution by 1000. The standard was checked after every 100 blood samples, with each triplicate sample of the standard counted three times. All blood samples were counted twice, and the average of the two counts was corrected for background, counting efficiency, and radioactive decay. (Counting efficiency ranged between 27.4 and 34.2%.) Repeated dosing. Fifteen adult cynomolgus females were divided randomly into three equal groups, and dosed orally with the equivalent of 10, 25, or 50 pg/kg body wt/day mercury as methylmercuric chloride (Experiment III). Doses were administered on Mondays, Wednesdays, and Fridays at seven-thirds of these levels; actual doses of 23.3, 58.3, or 116.7 pg/kg were thus administered three times per week. Methylmercury was dissolved in a Na2COj vehicle, and added to 10 ml of apple juice immediately before dosing. Monkeys drank the dosing solution immediately. Blood was sampled by femoral venipuncture every 14 days (on Wednesdays before dosing) and analyzed for total mercury by atomic absorption spectrophotometry. Monkeys were dosed until all reached at least 99% of their estimated equilibrium values using a one-compartment model (see below), and were then put on a breeding program. Blood levels are included for an individual monkey until it became pregnant or until approximately 120 weeks. Pharmacokinetic Models Single dosing. The concentration C(t) of mercury at time t in the blood of monkeys following a single oral dose of methylmercury was modeled as C(t) = A(e-“’ - e@)

(1)

C(t) = Ae-“’ + Be-‘* - (A + B)e-T’,

(2)

or

where A, B, (Y,@,and y are unknown parameters to be estimated on the basis of the experimental data. These pharmacokinetic models correspond to simple compartmental models involving one and two compartments, respectively (Gibaldi and Penier, 1975), and are useful in

METHYLMERCURY

PHARMACOKINETICS

describing the absorption and elimination of mercury in blood. During the postdistributive phase, C(f) is proportional to e? in both (1) and (2), where d = min{ol, fl) in (1) and min{cu, & r} in (2). In this terminal elimination phase, the half-time is given by t$ = (In 2)/6.

(3)

Both models (1) and (2) were fitted to the observed blood profiles for the two animals given a single oral dose of 500 rg/kg body wt (Experiment I). This was done using nonlinear least squares (Dixon, 1975) after applying a square root transformation to the observed blood levels in an attempt to stabilize the error variance over time. The significance of the improvement in fit of the twocompartment model relative to the one-compartment model was assessedusing an approximate F test in analogy with stepwise linear regression (Draper and Smith, 198 1). Estimates of the half-time during the postdistributive phase were subsequently derived through the use of (3). A similar analysis was carried out for each of the four animals given a single radioactive dose of methylmercury (Experiment II). Because of the lack of data during the absorption phase, the simplified models C(t) = Ae-“’

(4)

C(t) = Ae-“’ + Be@’

(5)

were employed. These models approximate those in (1) and (2), respectively, except during the absorption phase immediately postdosing. Repeated dosing. The models discussed previously can be extended to cover the case of repeated dosing. For example, following n daily doses of methylmercury, the blood profile corresponding to (4) is c(s) = AeP”( 1 - e-“,) (l-e-“) ’ where 0 6 s < 1 denotes the time in days following the nth dose. At steady state, the blood mercury concentration is given by P(s)

Ae-” = ___ (1 - e-“)

(7)

for 0 6 s < 1. The maximum and minimum blood levels occur at times s = 0 and s = 1, respectively, following administration of the last dose, with the average blood concentration between successivedoses being A/a. The model in (6) was modified as indicated in Eq. (A4) in the Appendix to permit dosing every Monday, Wednesday, and Friday and fitted to the observed blood proties for the 15 animals given repeated doses of methylmercury (Experiment III) using nonlinear least squares. (No transformation of the data was performed since the blood mercury concentrations observed in Experiment III varied little in comparison to those in Exper-

IN MONKEY

25

iments I and II, and no obvious pattern in the residuals was noted.) The significance of the improvement in fit realized through the use of more complex models analogous to (l), (2), and (5) was assessedusing approximate F tests. A background level of mercury is present for all animals in the three studies. The background measured in control animals during the repeated dosing study varied from 0.0 1 to 0.02 ppm. The curve fitting discussed above was repeated using the same models with a further additive constant which measured the background level. These models did not provide a significant (p > 0.05) improvement in fit of the curve over those considered above and did not have an appreciable impact on the estimate of the other parameters. The null hypothesis that the mean value ofthe parameter a in (6) does not change with dose was assessedusing an approximate F test’ based on a one-way analysis of variance of the estimated parameter values. The assumption that A is proportional to dose was assessedusing an F test for departures from linear trend. To evaluate the extent to which the steady-state blood levels in a long-term repeated-dosing experiment can be predicted on the basis of short-term single-dose studies, the average steady-state blood levels based on model (A4) as fitted to the observed data for those animals given an equivalent of 25 &kg/day were compared with those predicted on the basis of the models fitted to the results obtained in the two single-dose experiments. The observed and predicted steady-state levels were compared using t tests with an error term based on the variability between animals in the observed and predicted steadystate levels. To study the effects of dosing regimen on the steadystate behavior of the blood mercury levels, the weekly minimum, maximum, and average blood levels for a fixed weekly dose administered either daily, three times per week, or once per week were compared. These comparisons were based on model (A4), with parameters A and (Yequal to those of the individual monkeys dosed with the equivalent of 50 @kg/day.

RESULTS Single-Dose Experiments

While absorption is within 6 hr in Experiment of methylmercury remain 50 days after dosing (Fig.

largely complete I, detectable levels in the blood even 1). There are two

’ The F test is only approximate since the individual estimates of a are based on different periods of observation.

26

RICE ET AL. 1 EXPERIMENT

I

~500~g/kq)

1

l OBSERVED BLOOD LEVELS -FITTED Z-COMPARTMENT

1.0

MODEL

7 y-8

-2

& 3

2

Animal

-i :

t i. 0.1

. \

!z

“i.

i d

.

-1 0.01 0

I2 24 HOURs

rn I

I I I I I I, 111 IO 20 30 40 50 DAYS TIME

EXPERIMENT

.

IO4-

II

12 24 NOURS DOSING

(5OgClkg

1

l OBSERVED BLOOD LEVELS -FITTED 2-COMPARTMENT i “. MODEL 7

1061

105-

0 AFTER

l .* \

Animal

..

‘\

I

.

-

Animal

\

l . \*

2

l\.‘.

-* .

“.

DOSING

(DAYSI

FIG. 1. Pharmacokinetics of methylmercury in whole blood of monkeys given a single oral dose.

distinct segments in the elimination portion of the fitted curves, the first exhibiting rapid elimination and the second much slower. The two-compartment model (2) provides a

significant improvement in fit over the onecompartment model (1) (p < 0.002) in both cases. The halflife during the terminal elimination phase was about 15 days (Table 1).

METHYLMERCURY

PHARMACOIUNETICS TABLE

ESTIMATES

IN

1

OF THE PARAMETERS IN THE PHARMACOKINETIC MODELS FROM THE SINGLE DOSING EXPERIMENTS Model

EXpeliment 1

DClSe

Animal

500 M &s/kg w

body Mean

II

50 &/kg body wt (radiolabeled) equivalent to 25.3 pg Hg/kg body wtb

a Absorption b Based

phase on

1 &i

not

Mean

km)

0 (day-‘)

+ SE

0.92 1.56 1.24 f 0.32

0.39 0.18 0.29 + 0.10

0.045 0.048 0.046 f 0.001

+ SE

0.32 0.14 0.14 0.45 0.26 20.08

3.40 2.25 2.57 4.00 3.06 k 0.40

0.056 0.065 0.045 0.058 0.056 +0.004

0.062 0.068 0.059 0.066 0.064 &0.002

I 2 3 4

TO DATA

parameter B

A (ppm)

FITTED

0.42 0.27 0.34 * 0.08

1 2

27

MONKEY

(da& 13.7 31.8 22.75 zk 0.09 D D 0 0 u

tf (&YS) 15 15 15.0 + 0.4 11 10 12 10 10.9 f 0.3

modeled.

= 0.5 pg Hg (1 dpm/nl

= 0.2 157 ppm

The blood profiles observed during the elimination phase in Experiment II were similar in shape to those in Experiment I. The two-compartment model (5) provided a significant improvement in fit over the onecompartment model (4) (JJ < 0.00001) for all four animals, again due to the appearance of two distinct elimination phases. In this study the estimated half-life during the terminal elimination phase ranged from 10 to 12 days (Table 1). To determine if the differences in halftimes between Experiments I and II were due to the lack of availability of data during the absorption phase in Experiment II or the extended duration of data collection compared to Experiment I, the data were reanalyzed omitting data collected during the first 6 hr in Experiment I and after 49 days in Experiment II. The results obtained were comparable to those in Table 1.

Repeated Dosing The blood mercury levels for the monkeys in Experiment III generally increased over the first 7-12 weeks and subsequently pla-

Hg).

teaued (Fig. 2). Plateau blood levels were approximately 0.2-0.3 ppm for animals given 10 pg/kg/day, 0.6-0.8 at 25 pg/kg/day, and 1.3- 1.7 ppm for animals given 50 &kg/day (Table 2). In a few cases an increasing trend was still apparent at the end ofthe data collection period. However, these were monkeys for which the data covered a comparatively short time period, and for which further data (during or after pregnancy) revealed a plateau in blood mercury levels as observed in the other monkeys. The one-compartment model in (A4) provided a reasonable fit (Fig. 2), with more complex models failing to provide a significant improvement in fit (p > 0.05) except in the instances mentioned above. Although a two-compartment model was identified in Experiments I and II, the two-compartment model is highly unstable when fitted to repeated-dosing data of this type, in which the absorption and elimination phases are not readily observable. Thus, the simple model in (A4) was used here for descriptive purposes. Under this model, estimates of the time taken to reach 95% of the mean steady-state blood level ranged from 47 to 127 days, with the overall mean being about 92 days. There

28

RICE

t

. : .’ * * . ... 1’ . II :-

ET AL.

METHYLMERCURY

PHARMACOKINETICS

29

IN MONKEY

TABLE 2 E~TIMATESOFTHEPARAMETERSINTHEPHARMACOK~NETICMODELFITTEDTOTHEDATA FROMTHEREPEATEDDOSINGEXPERIMENT

Dose” (&kg/day)

Animal

Period of observation (weeks)

A (mm)

01(day-‘)

Predicted steadystate blood concentration, weekly mean 6-x-m w/W

Model parameter

Estimated time to reach 95% of the steady-state blood (days) 52 105 88 88 47 76tll

10

1 2 3 4 5 Mean + SE

114 54 102 102 44

0.030 0.019 0.026 0.019 0.042 0.028 f 0.005

0.057 0.029 0.034 0.034 0.064 0.044 i 0.007

0.23 0.29 0.31 0.23 0.28 0.27 t 0.02

25

1 2 3 4 5 Mean +- SE

66 102 54 58 102

0.042 0.056 0.049 0.035 0.063 0.049 -t 0.005

0.027 0.036 0.028 0.024 0.034 0.030 + 0.002

0.64 0.66 0.73 0.64 0.80 0.69 + 0.03

109 83 106 127 88 103* 8

50

1 2 3 4 5 Mean f SE

54 44 40 36 70

0.133 0.103 0.079 0.100 0.142 0.111-+0.005

0.032 0.028 0.025 0.030 0.044 0.032 f 0.003

1.78 1.60 1.38 1.43 1.39 1.51 kO.08

95 109 120 99 68 98+ 9

u Administered in three equal doses each week.

is no evidence that CYvaried with dose nor that A is not proportional to dose (p > 0.12 in both cases). Thus, no evidence of dose-dependent or nonlinear kinetics is provided by these data over the range of doses studied.

25 pgjkgjday upward or downward, tively.) These predictions are both cantly different (p < 0.05) from the state level of 0.69 + 0.03 obtained in ment III.

respecsignifisteadyExperi-

Prediction of Steady-StateBlood Levels

Dosing Regimen

The average weekly steady-state blood level predicted at a dose level of 25 pg/kg/day based on the model fitted in the first of the two single-dose experiments (Experiment I) is 0.33 + 0.09 ppm. Similar predictions are obtained even had this study been terminated at 20 days. The estimated steady-state blood level based on Experiment II is 0.94 -+ 0.05 ppm. (Predictions at 50 and 10 Ilg/kg/day are readily obtained by scaling the predictions for

The variation in steady-state blood levels predicted using Eq. (A4) were substantially different depending on whether dosing was daily, triweekly, or weekly (Table 3). Under daily dosing, the difference between the maximum and minimum blood concentrations ranged between 0.03 and 0.06 using the parameters from the five monkeys in the 50 pg/ kg/day group. Dosing three times per week produces swings in blood level between 0.10

30

RICE ET AL. TABLE 3 STEADY-STATEBLOODPROL~LESPREDI~EDUNDERDIFFERENTREPEATEDDOSINGREGIMENS

Steady-state blood level (ppm) Dosing interval

Monkey”

Daily

Monday, Wednesday, and Friday

Weekly

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

Weekly minimum 1.76 1.58 1.36 1.40 1.36 1.70 1.54 1.33 1.36 1.30 1.60 1.45 1.26 1.28 1.18

Weekly mean

Weekly maximum

Difference (max - min)

1.78 I .60 1.38 1.43 1.39 1.78 1.60 1.38 1.43 1.39 1.78 1.60 1.38 1.43 1.39

1.81 1.62 1.39 1.45 1.42 1.87 1.67 1.43 1.49 I .48 1.99 1.76 1.50 1.58 1.61

0.05 0.04 0.03 0.05 0.06 0.17 0.13 0.10 0.13 0.18 0.39 0.32 0.24 0.30 0.43

’ Based on the values ofA and 01in Table 2, for monkeys administered 50 &kg/day.

and 0.18 ppm, while dosing only once a week results in changes between 0.24 and 0.43 ppm. While weekly dosing produces a lower minimum blood level, it also produces a higher maximum. Depending on the value of A, the maximum could easily be over 2.0 ppm, while the average blood level for the group is 1.5 ppm. As indicated in Fig. 2, the predicted maximum blood levels could well be exceeded due to complex physiological processes resulting in systematic departures from the blood profiles expected under the simple pharmacokinetic model used here. DISCUSSION Based on the single-dose studies, it appears that absorption of methylmercury from gut is rapid, and that kinetics in blood are best described by a two- rather than one-compartment model. The elimination curve for this model involves two distinct exponential components corresponding to an initial rapid

elimination phase followed by a slower terminal phase. The first of these two elimination phases is not apparent under the repeateddosing schedule employed here due to the fact that only one blood sample was taken between successive doses. The kinetics of methylmercury in blood of humans are usually described by a single halftime, although tracer studies in humans also reveal two-compartment kinetics, with a short initial half-time (Aberg et al., 1969; Miettinen et al., 197 1). This short half-time probably represents uptake into target organs. The major half-time in blood predicted from the single-dose studies in the present experiment was lo- 15 days. Blood half-lives of 30 days have been reported for rhesus macaques (Finocchio et al., 1980), 20 days for pigtail and stumptail macaques (Evans et al., 1977), and 50 days for squirrel monkeys (Berlin et al., 1975a). Tracer studies indicate that the half-time in human blood is 49- 164 days (total of 18 individuals) (Miettinen et al., 1971; Aberg et al., 1969), while whole-body

METHYLMERCURY

PHARMACOKINETICS

estimates range from 33 to 189 days (Birke et al., 1972; Skerfving, 1974; Bakir et al., 1973), with evidence for a bimodal distribution (AlShahristani and Shihab, 1974). The shorter half-time of mercury in blood of the monkeys in the present study compared to that in humans would result in a considerably lower blood level in monkeys than in humans ingesting the same amount of methylmercury. The average predicted values of steadystate blood levels in the single-dose studies were markedly different from each other, with none being an adequate predictor of blood mercury levels actually achieved under conditions of repeated dosing. One estimate was based on a tracer study with radioactive mercury, while the other utilized a relatively high dose of cold mercury. Although the dose used in Experiment I was high relative to the doses used in Experiment III, the dose used in Experiment II was identical to the intermediate dose in Experiment III. Thus, the possibility of dose-dependent kinetics is probably not sufficient to explain this discrepancy. Moreover, there was no evidence of dose-dependent kinetics within the range of doses and blood levels in Experiment III, which exceeded the blood level achieved in Experiment I. The relatively large variation in kinetic parameters between individuals must be considered in relation to dosing regimen. Under a daily dosing regimen, there would be little difference between animals in the change in blood level between doses. Under longer dosing intervals, however, the difference could be considerable, depending on the parameters for each individual. Dosing intervals of once per week are not atypical in primate studies (Berlin et al., 1975a,b; Garman et al., 1975; Evans et al., 1977; Kato et al., 1981). Blood is typically drawn for mercury analysis before the next dose, so that the peak blood mercury level is not determined. In addition, a number of studies have used initial high doses to achieve the desired blood levels more quickly, followed by lower doses (Evans et al., 1977; Garman et al., 1975; Hellberg and Ny-

IN MONKEY

31

Strom, 1972) or just high doses for short periods (Shaw et al., 1975; Kawasaki et al., 1986). Unspecified, variable-dosing schedules have also been utilized (Berlin et al., 1975b). The crucial issue is not the variation in blood levels per se produced by any dosing regimen, but rather the effect of these variations on the target organs. These are unknown, both in terms of what effects changes in blood level have on changes in levels in target organs, and what effects these fluctuations have on pathology in the target region. However, it is well established that differences in dosing regimen can result in marked differences in signs of intoxication, ratio of brain mercury to blood mercury, and pattern of neuropathology (Kawasaki et al., 1986; Shaw et al., 1975; Berlin et al., 1975a; Hellberg and Nystrom, 1972; Sato and Ikuta, 1977; Evans et al., 1977). The ingestion of high doses over a short period can result in much more severe intoxication than ingestion of lower doses chronically, so it seems plausible that spikes and troughs in mercury levels in brain may also have differential effects compared to a steady level of the same average value. Differences in dosing procedures must be considered in interpretation of experimental data, as well as effects of exposure in humans. This is particularly true of agents with steep dose-effect curves, such as methylmercury, where small differences in blood (or target organ) levels may result in large differences in the effects of the agent. APPENDIX PHARMACOKINETICMODELSFOR REPEATEDDOSINGWITHUNEQUAL DOSINGINTERVALS

This appendix describes how the blood profiles under repeated dosing may be derived when dosing is done triweekly with unequally spaced doses. While details will be presented only for the one-compartment model with intravenous dosing, the same

32

RICE

ET AL.

general procedure is applicable for any comwhereO
(A2)

Similarly, after the third dose (4 < t < 7) C(t) = A( 1 + eP20 + e-4cl)ePrr= A[( 1 - e@)/ (1 - ee2Di)]epsa (0 =Ss < 3).

(A3)

Continuing in this fashion one can show that after the nth dose in the mth week c(t)

= A ( [( 1 - eP)/( X (e+

7(m-2)a

(e-2wb

+ +

1 - e-2n)]e-3a e-7(m-3)n

e-w-2)a

+

. .. +

+ . . . +

G., AND SNIHS, J. 0. (1969). mercury (203 Hg) compounds

Metabolism of methylin man. Arch. Environ.

Health 19,478-484. AL-SHAHRISTANI, H., ANDSHIHAB, K. M. (1974). Variation of biological half-life of methylmercury in man.

Arch. Environ. Health 28,342-344.

BAKIR,

F., DAMLUJI, S. F., AMIN-ZAKJ, L., MURTADHA, M., KHALIDI, A., AL-RAWI, N. Y., TIKRITI, S., DHAHIR, H. I., CLARKSON, T. W., SMITH, J. C., AND DOHERTY, R. A. (1973). Methylmercury poisoning in Iraq. Science181,230-241. BERLIN, M., CARLSON, J., AND NORSETH, T. (1975a). Dose-dependence of methyl-mercury metabolism.

Arch. Environ. Health 30,307-3 13. l)e-2(n-1)a

l)}e-“”

= A { [( 1 - e@“)/( 1 - e-2a)]eP3a x ( 1 _ e-7(m-l)a)/( 1 _ e-7n)e-2(“-lb + ( 1 - eP2”“)/( 1 - e-2n)}e-sol

(A4)

whereO
(A5)

BERLIN, M., GRANT, C., HELLBERG, J., HELLSTROM, J., AND SCHUTZ, A. (1975b). Neurotoxicity of methylmercury in squirrel monkeys. Arch. Environ. Health 30,340-348. BIRKE, G., JOHNELS, A. G., PLANTIN, L. O., SJ& STRAND, B., SKERFVING, S., AND WESTMARK, T. ( 1972). Studies on humans exposed to methylmercury through fish consumption. Arch. Environ. Health 25, 77-91. BURBACHER, T. M., MONNET~, C., GRANT, K. S., AND MOT-~ET, N. K. (1984). Methylmercury exposure and reproductive dysfunction in the nonhuman primate.

Toxicol. Appl. Pharmacol. 75, 18-24. CHEN, W., BODY, R. L., AND MOTTET, N. K. (1983). Biochemical and morphological studies of monkeys chronically exposed to methylmercury. J. Toxicol. Environ. Health 12,407-4 16. DIXON, W. J. (Ed.) (1975). BMDP Biomedical Computer Programs. Univ. of California Press, Berkeley. DRAPER, N., AND SMITH, H. (198 1). AppIied Regression Analysis, 2nd ed. Wiley, New York. EVANS, H. L., GARMAN, R. H., AND WEISS, B. (I 977). Methylmercury: Exposure duration and regional distribution as determinants of neurotoxicity in nonhuman primates. Toxicol. Appl. Pharmacol. 41,15-33.

METHYLMERCURY

PHARMACOKINETICS

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