Mercury Monkey Brain Delayed EffectAge-Related Increase in Auditory Impairment in Monkeys Exposed in Utero plus Postnatally to Methylmercury

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TOXICOLOGICAL SCIENCES 44, 191-196 (1998)

ARTICLE NO. T X9 82 48 7

Age-Related Increase in Auditory Impairment in Monkeys Exposedin Utero plus Postnatally to Methylmercury

Deborah C. Rice1

Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Protection Branch, Health Canada, Ottawa, Canada

Received January 26, 1998; accepted May 1, 1998

Age-Related Increase in Auditory Impairment in Monkeys Ex-posed in Utero plus Postnatally to Methylmercury. Rice, D. C.(1998). ToxicoL Sri. 44, 191-196.

Hearing impairment an d deafness have been reported as a resultof developmental and adult exposure to methylmercury; however,objective assessment of auditory function is generally lacking. Thisstudy extends previous research in our laboratory in which mon-keys exposed to methylmercury from birth to adulthood exhibitedhigh-frequency hearing impairment. Monkeys (Macaca fascicu-laris) were exposed throughout gestation and postnatally until 4years of age to 0, 10, 25, or 50 ftg/kg/day mercury as methylmer-curic chloride. When they were 11 and 19 years of age, pure-tonedetection thresholds for six frequencies between 0.125 and 31.5kHz were determined by means of a psychophysical (behavioral)procedure. At 19 years of age, all five methylmercury-exposedmonkeys exhibited elevated pure-tone thresholds compared withcontrols. Impairmen t was generally observed across the full rangeof frequencies. Comparisons of performance at 11 and 19 yearsrevealed relatively greater deterioration in function in treatedcompared with control monkeys. These results extend previously

reported evidence of deficits in auditory function produced bypostnatal methylmercury exposure, and describe a pa ttern of def-icit across frequencies different than that observed in the previousstudy. This study also provides evidence for development or ac-celeration of impairment of auditory function during aging as aconsequence of developmental methylmercury exposure, c IWS

Sod«7 of Toxicology.

Hearing deficits are a frequent result of methylmercury

poisoning in adults (Al-Damluji et al, 1976; Harada, 1968,

1977). Assessment of pure-tone detection thresholds, tested in

the range of speech frequencies (0.5-2 kHz), revealed hearing

impairment in half the ears tested (Ino and Mizukoshi, 1977).Severe hearing impairment, deafness, and delayed speech de-

velopment have been reported as a result of in utero exposure

to methylmercury (Marsh et al, 1980; Amin-Zaki et al, 1974,1979; Brenner and Snyder, 1980). However, the methodology

used to assess hearing in these studies was unspecified, and

results of assessments were not provided. More recently, a

1 Present address: 785 Main Rd., Islesboro, ME 04848. E-mail: ricekrwc®

midcoasLcom.

prospective study in a fish-eating population in the Seychelles

Islands reported deficits in auditory com prehension in children

with low exposure to methylmercury (Myers et al, 1995).

Since auditory function per se was not assessed, it is not known

whether this finding represents sensory impairment or some

other nervous system deficit.

In humans, developmental exposure to methylmercury pro-

duces a pattern of neuropathology different from that observedin adults (Takeu chi and Eto, 1975; Takeu chi, 1968). In adults,

deep sulci are preferentially damaged, while in utero exposure

results in damage that is much more uniform throughout the

brain. Infantile exposure results in a pattern of damage that is

intermediate between these patterns. The adult macaque mon-

key exhibits central nervous system pathology similar to that of

adult humans after exposure to methylmercury (Evans et al,

1977; Shaw et al, 1975; Garman et al, 1975). While the

auditory cortex has not been specifically examined after meth-

ylmercury exposure, temporal cortical damage has been ob-

served in both monkeys (Garman et al, 1975) and humans

(Takeuchi et al, 1962). Primary auditory cortex lies within the

fissure of the superior temporal gyrus and is thus a goodcandidate for preferential damage by methylmercury following

adult or infantile exposure (Takeuchi and Eto, 1975). In utero

exposure may be expected to produce diffuse damage to audi-

tory cortex.

There is evidence for delayed or accelerated neurotoxicity

during aging as a consequence of previous methylmercury

exposure (Rice, 1996). In an important study including more

than 90% of patients diagnosed with Minamata disease (MD)

20-30 years previously, it was reported that the ability to

independently eat, bathe, dress, wash the face, and use the

toilet decreased in an age-related manner in MD patients com-

pared with age-matched controls (Kinjo et al, 1993). In otherwords, there was an interaction between aging and previous

exposure to methylmercury. In a long-term follow-up study in

persons previously diagnosed with MD, it was reported that

auditory function had worsened (Harada, 1995). A "chronic"

MD was also identified that had a different pattern of signs than

early-onset MD and was characterized by a high incidence of

somatosensory impairment (glove and stocking hypoethesia)

and auditory impairment. Harada (1995, p. 14) differentiated

three patterns of worsening of signs of MD: "gradually pro-

191 1096-6080/98 $25.00

Copyright O 1998 by the Society of Toxicology.All rights of reproduction in any form reserved.



192 DEBORAH C. RICE

gressive type, delayed onset type, and escalator progressive

type with aging." In our laboratory, we observed overt toxicity

manifested as clumsiness at 13 years of age in a cohort of

monkeys exposed to methylmercury from birth to 7 years

(Rice, 1989a). These monkeys also developed additional signs

of methylmercury-induced toxicity as they approached 20

years of age that had not been present when they were younger

(Rice, 1996).We previously reported high-frequency hearing loss in the

cohort of monkeys dosed with methylmercury from birth to 7

years of age and tested at 14 years (Rice and Gilbert, 1992).

The current study extends this research by assessing auditory

function in monkeys exposed in utero to about 4 years of age

to the same or lower doses as those in the previous study.

Pure-tone detection thresholds were determined across most of

the hearing range of macaque monkeys using a psychophysical

(behavioral) procedure. All individuals were tested at 19 years

of age, while some individuals were also tested at 11 years,

allowing comparison of auditory function at middle age and

during aging.

METHODS

Subjects. Methylmercury-exposed monkeys (Macaca fascicularis) were

exposed in utero and continuing after birth until about the age of puberty. The

mothers of the infants were dosed three times per week with the equivalent of

10, 25, or 50 /xg/kg/day of mercury as methylmercunc chloride added to a

small amount of juice. When at least 90% of the estimated blood equilibrium

value based on a one-compartment model was reached (Rice, 1989a), females

were bred to untreated males. Infants were separated from their mothers at

birth and dosed with the same nominal dose their mothers had received,

administered 5 days a week. Dosing was discontinued when offspring were

3.5-4.5 years of age. Five infants were born in the high dose, two at the

intermediate dose, and one at the low dose. Two monkeys from the high-dose

group were alive at 11 years of age when auditory function was first assessed,as were the three monkeys at the lower doses. Infants were bom with blood

mercury concentrations about 1.8 times higher than those of their mothers,

which decreased with a half-life of 2-3 months for the monkeys in the current

experimen t to steady-state concentrations that were m aintained for the duration

of exposure. Modeling of blood mercury kinetics was carried out after termi-

nation of methylmercury exposure (Rice, 1989a), and included estimated

concentration at birth and under steady-state conditions and the half-life of

elimination following cessation of methylmercury exposure (Table 1). No

monkey ever received any known ototoxic agent including aminoglycoside

antibiotics. Overt signs of methylmercury toxicity such as nystagmus, obvious

visual impairment, tremor, clumsiness, or ataxia were not observed in any

monkey tested in this experiment.

Equipment and calibration procedure. Individual sine-wave frequencies

were generated by a Krohn-Hite (Avon, MA) oscillator (Model 4141R).

Sine-wave tones were fed through an attenuator to a rise-fall pulse shaper

(Model 584-04, Coulbourn Instruments, Lehigh Valley, PA), audio-mixer

amplifier (Coulbourn Model S82-24), and 40-dB attenuator to the earphone

(Sennheiser HD540 Reference Gold, Wedemark, Germany). Rise and fall time

was a 200-ms linear ramp. The linearity and absolute value of frequency and

amplitude were checked monthly. Headphone amplitude was calibrated using

Bruel and Kjaer (Naerum, Denmark) precision sound level meter Model 4230,

Bruel and K jaer sound measuring amplifier 26 10, Bruel and Kjaer artificial ear

Model 4153, and Bruel and Kjaer 0.5-in. condenser microphones 4134 (to

20,000 Hz) and 4136 (to 40,000 Hz). The calibration data were used to produce

a linear headphone response from 85 to 40,000 Hz.

TABLE 1

Subjects

Dose(ftg/kg/day)

50

25

10

0

Monkey No.

101102

116

118

104

117

120

Sex

FM

M

F

M

M

M

Mercury

concentration (ppm)

Birth

2.002.70

1.05

0.80

0.45

nd°

nd

Steady state

0.800.78

0.46

0.41

0.22

nd

nd

I

(days)

12.714.9

10.4

9.4

13.6

" Not detected.

Behavioral procedure. Monkeys were initially tested beginning at 11

years of age, at which time complete data were obtained from treated monkeys

102, 116, and 118 and control monkeys 117 and 120. High-dose monkey 101

failed to generate reliable data after almost a year of training. Low-dose

monkey 104 generated three reliable threshold s, at which time stereotypic

behavior made further testing unadvisable. Monkey 101 subsequently easilylearned a somatosensory task using the same psychophysical procedure as in

the auditory experiment, and 104 also performed well on the somatosensory

task with no behavioral problems. When monkeys were 19 years old, auditory

thresholds were redetermined. Individuals who had generated complete data at

11 years of age were retested in the right only, while 101 and 104 were tested

in both ears. The second assessment of all individuals was necessary for

comparisons to be age-matched. Reassessmen t also provided the opportunity to

compare possible degradation of auditory function over time in control and

methylmercury-trcated monkeys.

Schedule control and data acquisition were by means of a behavioral

notation language (Gilbert and Rice, 1979) run on a Nova 4 minicomputer

(Data General, Southboro MA ). Data were collected as interevent times so that

the session could be reconstructed from the raw data. The monkey sat in a

primate chair, restrained at the neck and the waist, inside a sound-attenuating

cubicle. Earpieces attached to the primate chair were precisely positioned overeach ear for delivery of the auditory signal. Different-size chairs were used for

individual monkeys as appropriate. The monkey initiated a trial by touching a

stainless-steel bar which completed a ground loop sensed by the computer.

This resulted in a signal light facing the monkey changing from red to green

and initiated a variable foreperiod of 2, 3, 5, or 7 s, chosen randomly within

each group of four trials. After the foreperiod, the tone to be detected was

delivered monaurally. The monkey's response indicated detection or lack of

detection of the stimulus (yes-no response paradigm). Release of the bar

within 1.5 s resulted in offset of the tone and delivery of 0.5 ml of apple juice

followed by a 3-s intertrial interval (111). Failure to release the bar within 1.5 s

resulted in offset of the tone, the signal light changing from green to white, and

initiation of a 10-s time-out (TO) period. Premature release of the bar before

tone onset resulted in a TO period and a repeat of the trial. Sessions comprised

100 (11 years) or 50 (19 years) completed threshold testing trials. Thirty-three

(11 years) or 16 (19 years) additional trials were catch trials with a 7-s

foreperiod in which a tone 12 dB above that of the previous trial was used asthe signal tone. Failure to release the bar within 5.0 s of the onset of the tone

resulted in a TO period; release resulted in reinforcement Monkeys were

tested one session per day, 5 days per week. Monkeys were given a specified

amount of water after each session, at least 50 ml/kg.

Only one ear and one frequency were tested within a session. No sound w as

delivered to the other car. The method of stimulus presentation was the

transformed up-down psychophysical method. The session began with a

high-intensity sound that was above the threshold for that individual. Starting

sound levels varied between 44 and 106 dB depending on the frequency being

tested and auditory sensitivity of the individual. The first 15 correct responses



AUDITORY IMPAIRMENT IN METHYLMERCURY-EXPOSED MONKEYS 193

CD

•oao

Xc/iLL J

a:

— HGHT19YW

—KHTIIWS

—uniitHS

117(COHTIK)l) 120(COtnKOQ

r-

4B 1 t» B Hi N S JU

FREQUENCY (kHz)

FI G . 1. Auditory threshold functions for control monkeys 117 and 120 in

which both ears were tested at 11 years of age and the right ear at 19 years.

Each point represents the mean ± SEM for the three sessions with the lowest

threshold.

each decreased the amplitude by 3.0 dB; subsequent correct responses de-

creased the amplitude by 3.0 dB with a probability of one-third. Each failure

to respond to the tone increased the amplitude for the next (noncatch) trial by

3.0 dB. This schedule results in threshold being estimated at 75% correctresponses.

A session was included for threshold determination if the monkey made a

premature release in fewer than 10% of noncatch trials and made either a

premature release or a failure to release on a total of fewer than 15% of catch

trials. Threshold was calculated by determining each crossing point for the last

60 (11 years) or 30 (19 years) noncatch trials of a session and determining the

median. A crossing point was defined as the mean decibel value between each

pair of changes of direction in am plitude; i.e., between w hen amplitude began

increasing as the result of an error and decreasing as the result of a correct

response according to the specified schedule criteria, or vice versa. A graph of

the amplitude across trials was also printed for each session. In almost all cases

the crossover points for the trials included for threshold determination were

characterized by a lack of slope, i.e., the threshold drifting neither up nor down

Whether the performance was stable was determined by visual inspection.

Sessions that did not meet these criteria were excluded. A threshold for eachfrequency for each ear was calculated as the mean of the lowest three daily

thresholds of five good (as defined above) sessions. Sessions w ere run at each

frequency until five sessions that met inclusion criteria were obtained. Fre-

quencies tested were 0.125, 1.0, 4.0, 10.0, 25.0, and 31.5 kHz. The order of

testing was such that adjacent frequencies were tested sequentially, beginning

at 4 kHz and moving up or down. This sequence was followed to maximize

practice effects. Treated and control monkeys at each of the two ages were

tested during the same period to ensure identical experimental conditions.

RESULTS

There were no differences between control and treated mon-

keys in measures of schedule control. Median reaction times

were 550-750 ms irrespective of foreperiod value.During assessment at 11 years of age, the two control

monke ys displayed psychophysical functions that are typical of

macaque monkeys, as discussed previously (Rice and Gilbert,

1992) (Fig. 1). Thresholds were elevated at the lowest and

highest frequencies, and generally flat in between. When re-

tested at 19 years of age, control monkey 117 had slightly to

moderately elevated thresholds in the right ear at all frequen-cies, ranging from about 3 to 17 dB (Fig. 1) (Table 2). In

contrast, control monkey 120 exhibited an 8.5-dB elevation in

threshold at 1 kHz w hile thresholds for most other freq uencies

were lower than at 11 years.

High-dose monkey 101 had extremely elevated thresholds in

both ears at all frequencies at 19 years of age (Fig. 2). The

shape of her curve was also abnormal, with thresholds gener-

ally decreasing slightly as a function of increasing frequency.

High-dose monkey 102's thresholds were elevated in both ears

compared with controls at all but the highest frequency at 11years of age; at 19 years of age, the three higher frequencies

were impaired compared with performance at 11 years. Mid-

dle-dose monkey 116 had an elevated threshold at 10 kHz in

the left ear at 11 years, while the threshold at 25 kHz in the

right ear was sufficiently elevated that 31.5 kHz was not tested.

At 19 years of age, high frequencies in the right ear were even

more elevated, compared with controls, than they had been at

11 years. For middle-dose monkey 118, thresholds in the right

ear appeared normal at 11 years, while the left ear had elevated

thresholds at the three lowest frequencies. When retested at 19

years of age, she exhibited elevated thresholds in the right ear

compared with the control monkeys at all but the highest

frequency. Low-dose monkey 104 exhibited elevated thresh-

olds in both ears at 19 years of age at all frequencies but the

highest, with the right ear being more impaired than the left.

The three data points collected w hen he w as 11 years of age, on

the other hand, were within the range of control values.

Comparison of the differences in auditory function between

the ages of 11 and 19 years provides some evidence for

differential impairment as a function of aging between control

and methylmercury-exposed monkeys (Table 2). Monkey 102

and, to a lesser extent, monkey 116 exhibited a selective

increase in impairment at higher frequencies, a pattern not

observed in controls. Monkey 118 had no increase in threshold

at 31.5 kHz between 11 and 19 years, while thresholds at mostother frequencies were relatively more elevated than those of

controls. Similarly, 104 had apparently normal auditory func-

tion for the frequencies tested at 11 years, while thresholds in

both ears were elevated compared with controls at 19 years,

with a differential in the right ear of 40 dB for the frequency

tested at both ages.

TABLE 2

Threshold Difference in Right Ear between 11 and 19 Years

Frequency (kHz)

Dose

(Hg/kg/day) Monkey No. 0.125 1 10 25 31.5

<dB difference (19-11 years)

50

25

10

0

102

116

118

104

117

120

25

2.0

2 6 . 7

8.8

- 1 . 0

- 3 . 0

8.5

19.0

17.0

8.5

1.0

- 6 . 0

13.8

5.5

- 5 . 5

2 9 . 0

3.5

7.5

4 0 . 0

16.5

0

3 0 . 5

11.5

2 8 . 0

8.5

- 8 . 0

1 4 . 0

- 1 . 0

2.5

- 7 . 0



194 D EBO RA H C. RICE

102(50) " 6 ( 2 S )

RIGHT 19 YRS

LEFT 19 YRS

RIGHT 11 YRS

LEFT 11 YRS

in i 4 « a JU

FREQUENCY (kHz)

FI G . 2. Auditory threshold functions for five monkeys exposed to methylmercury throughout gestation to 4 years of age. Each panel is identified with the

appropriate monkey number and dose group (/xg/kg/day) in parentheses. Individuals in which complete functions were generated in both ears at 11 years of age

were retested in the right ear only at 19 years. Monkey 104 completed two points in the left ear at 11 years and one point in the right ear at 10 kHz (displaced

along the x axis for clarity). Thresholds presented as in Fig. 1.

DISCUSSION

The threshold curves of the control monkeys at 11 years of

age are in agreement with data in macaques from other inves-

tigators (Stebbins and Rudy, 1978; Stebbins et al., 1966; Pf-

ingst et al, 1978), being elevated at high and low frequenciesand comprising a relatively flat function between 1 and 25 kHz.

At 19 years, there was a tendency for the threshold at 1 kHz to

be elevated relative to thresholds between 4 and 25 kHz.

Norm al m onkeys can hear at least an octave higher than normal

humans; below 8 kHz the detection levels of humans and

macaques are identical (Owren et al., 1988).

When tested at 19 years of age, all five methylmercury-

exposed monkeys exhibited elevated thresholds for pure tones

compared with controls, in some cases 50 dB or more. There

was a lso a tendency for the functions of the treated monkeys to

be relatively flat as a result of relatively greater impairment

across the range of middle frequencies. It is tempting to spec-

ulate that the extreme hearing impairment of high-dose mon-

key 101 was responsible for her apparent inability to learn the

behavioral task necessary for auditory testing at 11 years.

Exposure to the identical behavioral task used in the current

study to assess somatosensory function enabled her to subse-

quently transfer that experience to the auditory task, even

though the auditory stimuli provided less obvious cues during

training than they did to other individuals. In a similar situa-

tion, a monk ey with severely im paired som atosensory function

was unable to learn the psychophysical task for assessment of

vibration thresholds until a large vibratory stimulus applied to

his upper arm was used as the detection stimulus during train-

ing (Rice and Gilbert, 1995).

Comparison of changes in auditory function between 11 and

19 years also provides evidence for an increase in impairment

in methylmercury-exposed monkeys relative to controls. This

is readily apparent for middle-dose monkey 118, whose right-

ear function deteriorated from within control range to clearly

above it during the 8-year period. The data available for

low-dose monkey 104 also indicated normal pure-tone detec-

tion thresholds at 11 years, which was clearly not the case at 19

years. There was a suggestion in the three monkeys that were

tested at the higher frequencies at both ages that higher fre-

quencies were relatively more impaired at the older age com-

pared with their younger data, although the absolute frequen-

cies were not necessarily more elevated compared with

controls. The hearing deficits observed in the current studypresumably represent irreversible hearing loss, since they were

present 7-15 years after cessation of methylmercury exposure.

Since auditory function was not tested during the period of

dosing, it is not known whether this loss appeared during the

period of methylmercury exposure or after cessation of dosing

for those individuals with thresholds already elevated when

first tested. However, it is also clear that individuals at the

lower doses displayed normal thresholds at some frequencies at



AUDITORY IMPAIRMENT IN METHYLMERCURY-EXPOSED MONKEYS 195

11 years that were elevated at 19 years. The data suggest that

impairment in the high-dose monkeys, in addition to being

more severe, also had an earlier onset than in the lower-dose

individuals: high-dose monkey 101 presumably had severely

compromised auditory function at 11 years of age, and high-

dose monkey 102 also displayed greater impairment compared

with controls at 11 years than did the three monkeys at the

lower doses. The apparent delayed neurotoxicity in some in-dividuals, and relative acceleration of neurotoxic impairment

in others, is consistent with findings in Japan (Harada, 1995).

Persons with early MD as a result of relatively high exposure

exhibited a worsening of some signs years after exposure to

methylmercury ceased, while other individuals with lower ex-

posure developed sings of methylmercury poisoning years after

cessation of exposure. It also extends previous findings in our

laboratory in a cohort of methylmercury-exposed monkeys in

which overt clumsiness was first observed at 13 years of age,

6 years after cessation of methylmercury exposure (Rice,

1989b).

Average mercury levels in whole blood of unexposed per-sons (i.e., with no known occupational exposure and with little

fish consumption) are in the range 4-20 ppb in various studies

(WHO, 1990), clearly much lower than blood mercury con-

centrations of the monkeys in the current study. However,

maximum blood mercury concentrations in adults who con-

sume significant am ounts of fish were reported to be as high as

800 ppb in individuals in Japan and 650 ppb in Sweden (W HO ,

1990). The steady-state blood mercury concentrations of all

five monkeys in the current study were at or below the maxi-

mum observed in humans and therefore are representative of

individuals from fish-eating populations. Mercury concentra-

tions at birth were higher than steady-state levels for all mon-

keys, which is also observed in humans (Amin-Zaki et al,1974, 1976). Even these acute peak levels were below the

maximum in adults in the above studies for two of the mon-

keys. Brain:blood mercury ratios following chronic methyl-

mercury exposure in monkeys range from 2.5 to 3.0 (Bur-

bacher et al., 1990; Rice, 1989c). While the brain:blood ratio

has been reported to be greater than this in humans (Burbacher

et al., 1990), this may be an artifact of delayed sampling

(death) following cessation of methylme rcury ex posure and the

longer half-life of mercury in brain com pared with blood (Rice,

1989c). In any event, mercu ry levels in the target organ (brain)

in the monkeys in the current study during dosing were prob-

ably similar to those of highly exposed humans.

The site(s) of damage responsible for the deficits observed in

the current study is unknown. While hearing impairment and

even deafness have been observed as a consequence of meth-

yrmercury exposure in humans since the 1960s, pathological

assessment of human or monkey tissue has not included the

auditory system. While a few studies have been performed in

other animal models (Ramprashad and Ronald, 1977; Anniko

and Sarkady, 1978; Falk et al., 1974; Wassick and Yonovich,

1985), exposure was acute high dose, which is probably irrel-

evant to the current study or typical human exposure. The

primary auditory cortex of the macaq ue lies in the depths of the

sylvian fissure on the middle one-third of the superior temporal

plane, while much of the rest of the superior temporal gyrus is

also auditory. Removal of the primary and surrounding cortex

in macaq ues results in deficits in pure-ton e detection threshold

(Heffner and Heffner, 1990). Con sistent with the results of the

current study, deficits were found to be greatest throughout the

middle range of frequencies, with high (32 kHz) and lowfrequencies relatively spared. The pattern of hearing loss in the

current study differs somewhat from the results of a previous

study in our laboratory in which monkeys were exposed to 50

pig/kg/day mercury as methylmercury from birth to 7 years of

age (Rice and Gilbert, 1992). In that study, high-frequency

hearing was preferentially damaged when monkeys were tested

at 14 years of age. The fact that impairment was observed over

most frequencies in some individuals in the current study may

reflect the diffuse pattern of damage observed following in

utero exposure (Takeuchi and Eto, 1975; Takeuchi, 1968). In

addition, however, there was evidence of relatively greater

impairment of higher frequencies with increasing age in someindividuals, suggesting that there may be more than one neu-

rotoxic process underlying the observed deficits.

The monkeys in the current experiment also underwent

assessment of visual function at 4 - 6 years of age and somato-

sensory function at 15 years of age. High-dose monkey 102,

middle-dose monkey 116, and low-dose monkey 104 exhibited

extreme impairment in spatial visual function, with the other

two monkeys having normal spatial vision (Rice and Gilbert,

1990). All treated monkeys displayed elevated thresholds for

detection of vibration at the fingertips, with no indication of a

dose-related deficit (Rice and Gilbert, 1995; Rice, 1996). As in

the current study, there was no indication of a cognitive deficit

as assessed by the monkeys' ability to learn the task andproduce orderly, stable psychophysical data.

SUMMARY

Monkeys exposed to methylmercury in utero to 4 years of

age exhibited elevated detection thresholds for pure tones at 11

and/or 19 years of age compared with age-matched controls.

Deficits were observed at most frequencies tested, including

the range of frequencies used in human speech. While blood

mercury levels during the period of exposure were at or near

the upper boundary of persons ingesting large amounts of fish,

a recent study in children in which deficits in auditory proces s-

ing were observed suggests that subtle deficits in auditory

function may result from lower-level exposure. There was

evidence for delayed neurotoxicity in the auditory system

being manifested between the ages of 11 and 19 years in

low-dose individuals and acceleration of existing impairment

in higher-dose individuals when compared with controls.

These findings extend previous data from our laboratory in

which delayed manifestation of overt toxicity was observed in

another cohort of methylmercury-exposed monkeys, and are

consistent with findings in persons with Minamata disease.



196 DEBORAH C. RICE

ACKNOWLEDGMENTS

The author thanks Virginia Liston, Bruce Martin, Wendy Cherry, and

Michelle Warankie Sutherland for expert technical assistance and Virginia

Liston for generation of graphics.

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