Hearing Research, 50 (1990) 211-224 Elsevier 211 HEARES 01469 Interaction of cisplatin and noise on the peripheral auditory system Michael Anne Gratton ‘, Richard J. Salvi ‘, Barton A. Kamen ’ and Samuel S. Saunders ’ ’ State University of New York at Buffalo, Department of Communrcatron Disorders and Sciences, Hearing Research L.ahoratocy. Buffulo, New York and ’ University of Texas Southwestern Medical Center, Departments of Pedratrics and Pharmacoloa. Dallas, Texas, U.S.A. (Received 14 February 1990; accepted 16 June 1990) The potentiation of cisplatin ototoxicity by noise was explored in the chinchilla. The effects of exposure to cisplatin alone, noise alone or concurrent exposure to both agents were compared in terms of the threshold shift of the auditory evoked potential and the amount of hair cell loss. The combination of cisplatin plus noise produced significantly more hair cell loss and hearing loss at the high frequencies than did either the noise or cisplatin alone when the noise level was 85 dB SPL or higher; no interaction was seen when the noise level was 70 dB SPL. The amount of the interaction, when present, was constant regardless of the noise level. These results indicate that moderate to high levels of noise can exacerbate cisplatin ototoxicity. Cisplatin; Ototoxicity; Noise/drug interaction; Evoked response; Hair cell loss; Hearing loss Introduction Cisplatin is an effective chemotherapeutic agent in the treatment of some cancers (Holleb, 1986). It is often administered on an out-patient basis with several weeks occurring between each course of treatment. Clearance of cisplatin from the body is incomplete, especially in the kidney (Litterst et al., 1979; Sharma and Edwards, 1984) and nephro- toxicity is the dose-limiting side effect of cisplatin (Borch, 1987). The cochlea also exhibits high affin- ity for cisplatin (Litterst and Schweitzer, 1984; Schweitzer et al., 1984) which can result in ototoxicity. The ototoxic hearing loss is permanent and cumulative in nature as the dose (Helson et al., 19778: Strauss et al., 1983) or duration (Vermorken et al., 1983) of the chemotherapy increases. Ototoxicity initially affects the struc- tures subserving high frequencies as reflected both Correspondence to: Michael Anne Gratton (Current address) Department of Otolaryngology, University of Texas South- western Medical Center, 5323 Harry Hines Blvd., Dallas TX 75235, U.S.A. FAX:(214)905-3143. by anatomical (Fleischman et al., 1975; Schweitzer et al., 1984) and physiological (Fausti et al., 1984) indices. The clinical incidence of cisplatin ototoxicity ranges from 20% to 90% (Kovach et al., 1973; Helson et al., 1978; Aguilar-Markulis et al., 1981; Fausti et al., 1984). Factors such as the mode of drug administration (Reddel et al., 1982; Vermorken et al., 1983) tumor site, age (Helson et al., 1978; Aguilar-Markulis et al., 1981), renal function and prior cranial irradiation (Grano- wetter et al., 1983; Baranak et al., 1988) have been suggested to influence both the incidence and degree of cisplatin ototoxicity. The interaction of cisplatin with other ototraumatic agents is another factor which can exacerbate the ototoxic effects. Cisplatin has been shown to interact additively with both the aminoglycoside antibiotics (Schweitzer et al., 1984) and diuretics affecting the loop of Henle (Brumett, 1981; Komune and Snow, 1981). Noise is another agent which could poten- tially exacerbate cisplatin ototoxicity. Several clinical studies (Aguilar-Markulis et al., 1981; Fleming et al., 1985) have suggested that patients with pre-existing cochlear hearing loss may de- 0378.5955/90/$03.50 0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
Transcript
Hearing Research, 50 (1990) 211-224
Elsevier
211
HEARES 01469
Interaction of cisplatin and noise on the peripheral auditory system
Michael Anne Gratton ‘, Richard J. Salvi ‘, Barton A. Kamen ’ and Samuel S. Saunders ’
’ State University of New York at Buffalo, Department of Communrcatron Disorders and Sciences, Hearing Research L.ahoratocy. Buffulo,
New York and ’ University of Texas Southwestern Medical Center, Departments of Pedratrics and Pharmacoloa. Dallas, Texas, U.S.A.
(Received 14 February 1990; accepted 16 June 1990)
The potentiation of cisplatin ototoxicity by noise was explored in the chinchilla. The effects of exposure to cisplatin alone, noise
alone or concurrent exposure to both agents were compared in terms of the threshold shift of the auditory evoked potential and the
amount of hair cell loss. The combination of cisplatin plus noise produced significantly more hair cell loss and hearing loss at the
high frequencies than did either the noise or cisplatin alone when the noise level was 85 dB SPL or higher; no interaction was seen
when the noise level was 70 dB SPL. The amount of the interaction, when present, was constant regardless of the noise level. These
results indicate that moderate to high levels of noise can exacerbate cisplatin ototoxicity.
Cisplatin is an effective chemotherapeutic agent in the treatment of some cancers (Holleb, 1986). It is often administered on an out-patient basis with several weeks occurring between each course of treatment. Clearance of cisplatin from the body is incomplete, especially in the kidney (Litterst et al., 1979; Sharma and Edwards, 1984) and nephro-
toxicity is the dose-limiting side effect of cisplatin (Borch, 1987). The cochlea also exhibits high affin- ity for cisplatin (Litterst and Schweitzer, 1984;
Schweitzer et al., 1984) which can result in
ototoxicity. The ototoxic hearing loss is permanent and cumulative in nature as the dose (Helson et
al., 19778: Strauss et al., 1983) or duration (Vermorken et al., 1983) of the chemotherapy increases. Ototoxicity initially affects the struc- tures subserving high frequencies as reflected both
Correspondence to: Michael Anne Gratton (Current address)
Department of Otolaryngology, University of Texas South-
western Medical Center, 5323 Harry Hines Blvd., Dallas TX
75235, U.S.A. FAX:(214)905-3143.
by anatomical (Fleischman et al., 1975; Schweitzer et al., 1984) and physiological (Fausti et al., 1984) indices.
The clinical incidence of cisplatin ototoxicity ranges from 20% to 90% (Kovach et al., 1973; Helson et al., 1978; Aguilar-Markulis et al., 1981; Fausti et al., 1984). Factors such as the mode of drug administration (Reddel et al., 1982; Vermorken et al., 1983) tumor site, age (Helson et al., 1978; Aguilar-Markulis et al., 1981), renal
function and prior cranial irradiation (Grano- wetter et al., 1983; Baranak et al., 1988) have been
suggested to influence both the incidence and degree of cisplatin ototoxicity. The interaction of cisplatin with other ototraumatic agents is another factor which can exacerbate the ototoxic effects. Cisplatin has been shown to interact additively with both the aminoglycoside antibiotics (Schweitzer et al., 1984) and diuretics affecting the loop of Henle (Brumett, 1981; Komune and Snow, 1981). Noise is another agent which could poten- tially exacerbate cisplatin ototoxicity. Several clinical studies (Aguilar-Markulis et al., 1981; Fleming et al., 1985) have suggested that patients with pre-existing cochlear hearing loss may de-
velop greater hearing loss from cisplatin than those with normal baseline hearing sensitivity. In con- trast, Laurel1 and Borg (1986), exposed guinea pigs to a high level broad-band noise for 15-20 minutes and administered cisplatin ten days later. They concluded that a pre-existing noise-induced hearing loss did not increase the risk of hearing loss over that caused by cisplatin alone. However, they did not determine if the hearing loss caused by concurrent exposure to noise and cisplatin was greater than that caused by either agent alone. Thus, the present study was designed to (1) evaluate whether concurrent exposure to cisplatin and noise causes more hair cell loss and hearing loss than either agent alone, and (2) to determine the minimal level of noise necessary for the inter- action between noise and cisplatin to occur.
Materials and Methods
Subjects Forty-seven adult cockle weighing between
450 and 550 grams were used as subjects. Six of the animals received cisplatin-alone; 21 were ex- posed to noise-alone (7 at 70 dB SPL, 7 at 85 dB SPL and 7 at 100 dB SPL) and 20 animals were exposed to the combination of cisplatin and noise (6 to cisplatin/70 dB SPL, 6 to cisplatin/85 dB SPL and 8 to cisplatin/lOO dB SPL).
Evoked response th~e~hoid me~~rem~nt Each animal was made monaural by surgical
destruction of the left cochlea and a chronic re- cording electrode was stereotaxically placed in the left inferior colliculus (Henderson et al., 1973; Salvi et al., 1982). Following 10 days of recovery, evoked response threshold testing was initiated. During the test procedure, the awake animal was placed in a single-walled booth (IAC 400) lined with sold-absorb~g foam. To ensure a constant orientation of the animal’s head within a calibrated sound field, the animal was placed in a restraining yoke (Blakeslee et al., 1978).
The tone burst stimuli (20 ms duration, 5 ms rise/fall, 100 ms inters~~us interval) used to elicit the evoked response were generated and shaped by a signal processing board (DSP 320, Forth, Inc.) located in a personal computer (IDS Turbo 88). The stimuli were then routed to a
custom mixer, followed by a programmable at- tenuator, transformer and a speaker (Realistic 1218). The speaker was mounted 38 cm in front of, and at 0” azimuth relative to the animal’s nose.
Evoked response recordings were obtained at 0.5, 1, 2, 4, 8, 11.2 and 16 kHz stimuli. The evoked reponse was amplified ( X 2000-5000), filtered (30 to 3000 Hz) and led to a 16 bit A/D converter in a personal computer {IDS Turbo 88). The re- sponse was sampled over 30 ms (300 points, 10,000 Hz rate) following onset of the stimulus. An ascending intensity series (5 dB steps) was em- ployed at each test frequency. Each averaged waveform consisted of 250 samples at each stimu- lus level. A response was considered to be a change in the evoked reponse from baseline activity dur- ing the 5 to 15 ms period following onset of the stimulus (Davis and Ferraro, 1984). Threshold was defined as the midpoint between the lowest inten- sity level at which an evoked reponse could be detected and the highest intensity level at which the reponse was absent. Five threshold measures were used to establish the mean pre-exposure and mean 30-day post-exposure audiograms. The dif- ference between the two mean data sets delineated the magnitude of the permanent threshold shift (PTS) caused by the experimental treatment. Ad- ditional threshold measures were also obtained at various times during and after exposure to the drug and/or noise. The PTS values from all animals in an experimental condition were aver- aged to obtain the group mean PTS audiogram.
Histology Following collection of the final 30-day post-
exposure threshold measures, each animal was sacrificed and the cochlea analyzed for hair cell damage using the surface preparation technique (Engstrom et al., 1966). The anesthetized animal was decapitated, the bulla quickly removed and opened to expose the cochlea. The stapes was removed and the round window membrane pierced after which cold 2.5% gluteraldehyde in a Verona1 acetate buffer (pH 7.4) was perfused through the round window opening. The cochlea was re- frigerated overnight with a second perfusion of the same solution during the next day followed by a second period of refrigeration. The cochlea was then post-fixed and stained via a slow perfusion of
213
cold 1% 0~0, in a Verona1 acetate buffer through the round window opening. After a 20-30 min staining period, the cochlea was placed in a 50% ETOH solution and then dehydrated one hour later to a 70% ETOH solution. Following drilling
to thin the otic capsule, the cochlea was immersed in a 50% solution of 0.7M EDTA (pH 8.0). The decalcified cochlea was microdissected and the
organ of Corti mounted in glycerin for micro- scopic study. The sensory epithelium was ex- amined at 400 x using Nomarski differential in- terference contrast microscopy to quantify the
number of missing outer (OHC) and inner (IHC) hair cells. The cells were considered present if the
cell body, cuticular plate and stereocilia were in- tact. Counts of missing cells by type were entered
into a personal computer (IDS Turbo 88), normal- ized (Bohne et al., 1986) and plotted as a function
of percent distance from the apex of the cochlea (Bohne and Carr, 1979) in order to obtain a cochleogram. Position in the cochlea was also
related to a specific frequency using a cochlea map (Eldredge et al., 1981). Cell data for all
animals in a group were averaged over 1% inter- vals to obtain a group mean cochleogram.
Experimental conditions and schedule The animals were divided into seven groups.
Six to eight animals per group completed all phases
of the study. A group was exposed to one of three experimental conditions: cisplatin-alone (N = 6), noise-alone (N = 7 for 70 dB SPL, N = 7 for 85 dB SPL, N = 7 for 100 dB SPL), or the combina-
tion of cisplatin and noise (N = 6 for cisplatin/70
dB SPL, N = 6 for cisplatin/85 dB SPL, N = 8 for cisplatin/lOO dB SPL).
Noise Condition. Three groups of animals were exposed to the noise-alone condition. The noise exposure consisted of an octave band of noise centered at 500 Hz (500 Hz OBN) presented at a level of 70, 85 or 100 dB SPL. The noise stimulus was generated and shaped using a signal processing board (DSP 320, Forth, Inc.) in a personal com- puter (IDS Turbo SS), and two filters (Krohn-Hite 355R, Technics SH8065). The signal was routed to a power amplifier (NAD 2200) and an exponential acoustic horn (JBL 24555). Calibration of the noise spectrum and level were made using a l/2 inch
NOISE GROUP
CISPLATIN GROUP
CISPLATIN AND NOISE GROUP
EXPOSURE SCHEDULE
WEEK 1 WEEK 2 WEEK 3
1234 5 6 71234 5 6 7
m NOISE
Fig. 1. Exposure schedule for the three experimental conditions
of the study.
condenser microphone (AC0 4136) and a sound level meter (Larson-Davis 800B). Measures of the
sound pressure level taken at six points within and
around the set of animal cages varied by less than 1.5 dB SPL. Additional measures of the noise level
were taken during and after each exposure session. The noise stimulus was presented continuously for
a five days followed by two days of rest. This cycle was repeated as illustrated in Fig. 1 for a
total of fifteen days noise exposure. During the noise exposure, six animals were housed in indi-
vidual wire cages (17.8 cm X 30.4 cm x 17.8 cm) located 45.7 cm beneath the edge of the acoustic horn and 45.7 cm above the floor of the re- verberant chamber (IAC single-walled booth). Free access to food and water was provided throughout the exposure.
Cisplatin condition. One group of animals was exposed to cisplatin-alone. The drug-alone ex-
posure consisted of intraperitoneal injections of
cisplatin at a dosage of 2.75 mg/kg of body weight for two consecutive days per week (Fig. 1) over a two week period. To avoid nephrotoxicity. the animals were hydrated with lactated Ringer’s (i.p. at a volume equal to 6% of body weight). The animals were hydrated five times daily during a 2.5 day period. The hydration period for each 2-day drug cycle began 6 hours prior to the first cisplatin injection and continued until 6 hours after drug injection on the second day.
Cisplatin and noise condition. Three groups of animals were exposed to the interaction condition. The parameters of the noise exposure and drug
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administration were as described above. The in- tensity level of the 500 Hz OBN was 70, 85 or 100 dB SPL. As depicted in Fig. 1, the interaction group received the 2-day cisplatin cycle during each 2-day rest period from the noise.
Nephrotoxicity measurement As a further measure of the effect of the cispla-
tin on the c~nc~Ila, the creatinine level of serum and urine samples were analyzed to determine if any changes in hearing sensitivity were due to, or preceded by, permanent renal damage. Urine sam- ples were collected every four hours during the 24-hour period preceding and following the drug ad~~stration, both in the animals exposed to cisplatin and hydration fluid (N = 6) or to the combination of cisplatin/hydration fluid/l00 dB SPL noise (N = 6) as well as in a group of chinchillas receiving only the hydration fluid with (N = 5) and without (N = 5) the 100 dB SPL noise exposure. The urine samples were re- frigerated until time of analysis. Samples of blood were obtained from the same animals at the time of sacrifice. The blood was allowed to coagulate and then was centrifuged (Beckman n-6) to ob- tain the serum. A quantitative, calorimetric de- termination of the creatinine level in each serum and urine sample was made using a commercially available diagnostic kit (Sigma SSS-AO) and a spectophotometer (Gifford 250).
Results
The preexposure evoked response threshold of the animals in this project were summed to com- pute the mean pre-exposure threshold and stan- dard deviation for each test frequency. The mean pre-exposure evoked reponse audibility curve was consistent with audibility values reported by Davis and Ferraro (1984) and Henderson et al. (1983) in normal-hearing chinchillas (Table I).
Threshold shifts during experimental treatment Hearing sensitivity was monitored before and
after each 2-day injection, as well as before and after each j-day period of noise exposure. The changes in hearing sensitivity at 500 Hz and 16,000 Hz which occurred during the experimental treat- ment are illustrated in Fig. 2. Each graph shows the hearing loss at the beginning (0. 168, 336 h) and end (120, 288, 456 h) of each S-day noise exposure. Administration of cisplatin (injections at 126, 146, 294, 314 h) did not cause any change in hearing sensitivity at 0.5 or 16 kHz as shown in panel A of Fig. 2. Likewise. exposure to 70 dB SPL noise (Fig. 2, Panel B) or to the comb~ation of cisplatin and 70 dB SPL noise (Fig. 2. Panel C) did not affect hearing sensitivity at 0.5 or 16 kHz. Exposure to the 85 or 100 dB SPL noise (Fig. 2, Panel B, upper), or to the cisplatin/85 dB SPL or
TABLE I
GROUP MEAN THRESHOLD AND STANDARD DEVIATION FOR PRE-EXPOSURE EVOKED RESPONSE MEASURE- MENTS AS A FUNCTION OF FREQUENCY COMPARED ACROSS STUDIES
HOURS 3F EXPOSURE HOURS OF EXPOSURE HOURS OF SXPOSURE
Fig. 2. Threshold shift at 500 Hz (upper) and 16,000 Hz (lower) during exposure to cisplatin (Panel A), an octave band of noise centered at 500 Hz at 70.85 or 100 dB SPL (Panel B) or the combination of cisplatin and noise (Panel C).
cisplatin/lOO dB SPL noise conditions (Fig. 2, Panel C, upper) created a hearing loss of ap-
proximately 36 dB, 45 dB, 39 dB and 50 dB respectively, at 500 Hz. The hearing loss was sta-
ble across test days 5, 12 and 19 (120, 288 and 456 h). The thresholds recovered 20-30 dB during the t-day rest period from the noise exposure (120-168 and 288-336 h).
At 16,000 Hz, a stable hearing loss of ap- proximately 10 dB or 37 dB also occurred across test days 5,12 and 19 (120, 288 and 456 h) during exposure to the 85 or 100 dB SPL noise (Fig. 2, Panel B, lower). Thresholds recovered approxi- mately 5 and 15 dB during the rest periods on days 5-7 (120-168 h) and 12-14 (288-336 h) from the 85 dB SPL and 100 dB SPL noise ex- posures respectively (Fig. 2, Panel B, lower). In contrast, concurrent administration of cisplatin/85 dB SPL noise or cisplatin/lOO dB SPL noise (Fig.
2, Panel C, lower) caused a progressive, but not statistically significant (0.05 > P > 0.01; student
t-test; t. 05(2n6 = 2.48) increase in hearing loss during the I9 day period of combined noise and cisplatin exposure (24-55 dB, 3’7 to 55 dB, respec- tively). Finally, partial recovery of hearing on days 7 and 12 (168 and 336 h) due to the 2-day rest
from noise was less during exposure to the cispla- tin/noise combination than during exposure to the noise-alone condition.
Recovery of hearing post-treatment Changes in the amount of temporary threshold
shift (TTS) were monitored at 1, 4, 48 (day 2), 169 (day 7) and 336 (day 14) hours post-exposure. The results (Fig. 3) at 500 Hz are representative of the trends seen in the low frequencies, while the data at 16,000 Hz are representative of the trends seen at the high frequencies (4-16 kHz). The threshold
shift data were analyzed using multiple regression.
The time of treatment measurement and the type of experimental treatment were found to interact
significantly (P < 0.001; multiple regression: F
= 13.19, N = 47, df = 3) in determining the amount of threshold shift. The slopes of the re-
covery functions when plotted in iog post-ex- posure time were flat following exposure to
cispfatin-alone, the 70 dB SPL noise-alone, or the
combination of cisplatin/70 dB SPL noise. This indicates that none of these treatments had a
delayed effect upon hearing sensitivity.. In con-
trast, the recovery functions of the remaining four treatment groups (100 or 85 dB SPL noise, or the
combination of cisplatin/G or 100 dB SPL noise) displayed negative slopes indicating increased
hearing sensitivity with increased post-exposure
time. The degree of threshold shift separated the four recovery functions from one another. In the
group exposed to 85 dB SPL noise-alone (Fig. 3, Panel B), the threshold at both 500 and 16,000 Hz
recovered to essentially normal hearing sensitivity. In the group exposed to the 100 dB SPL noise- alone, the 16,000 Hz threshold recovered com-
pletely (Fig. 3, Panel B, lower}, while the 500 Hz threshold showed a residuai loss of approximately 20 dB (Fig. 3, Panel B, upper). In contrast, the
groups exposed to the combination of cisplatin/85 dB SPL or cisplatin/lOO dB SPL noise (Fig. 3,
Pane1 C) showed greater loss of hearing im- mediately after exposure than did their noise-alone counterparts. Furthermore, there was tittle re-
covery in hearing at 16,000 Hz (Fig. 3, Panel C, lower). However at 500 Hz, the groups exposed to
the combination of cisplatin and noise (Fig. 3, Panel C, upper) showed about the same amount of hearing loss and recovery as their noise-alone
counterparts (Fig. 3, Panel B, upper). Thus in the
CISPLATIN f NOISE GROUPS ME?& TTS AT 16,000 Hz
Fig. 3. Temporary threshold shift at 500 Hz (upper) and 16,OOO Hz (lower) during exposure to cisplatin (Panel A), an octave band of noise centered at SO0 Hz at 70, 85 or 100 dB SPL (Panel B) or the combination of cisplatin and noise (Panel C).
217
high frequencies (4-16 kHz), exposure to the com- bination of cisplatin/lOO dB SPL noise or cispla- tin/85 dB SPL noise produced greater hearing loss and less recovery then either the noise-alone or cisplatin-alone control groups.
Permanent threshold shift
The mean permanent threshold shift (PTS) ob- tained at 30-days post-exposure was computed
across frequencies for each exposure group. The dose of cisplatin administered in this project
caused little or no hearing loss at any test frequency as seen in panel A of Fig. 4. The only group of animals which sustained any significant permanent hearing damage from the noise ex- posure (Fig. 4, Panel B) was the 100 dB SPL group in which 15-25 dB PTS was noted between 0.5
and 4 kHz. The frequencies at which hearing loss occurred agree with the spectrum of the 500 Hz OBN stimulus. The permanent changes in hearing
sensitivity for the 70 dB SPL and 85 dB SPL noise
groups were 10 dB or less. Likewise, the group exposed to the combination of cisplatin/70 dB
SPL noise (Fig. 4, Panel C) did not incur any significant change in hearing sensitivity as a result of the drug and noise exposure. In contrast, the cisplatin/85 dB SPL and cisplatin/lOO dB SPL groups (Fig. 4, Panel C) showed a significant permanent hearing loss. The hearing loss was greatest (30-40 dB PTS) at the high frequencies indicating that the interaction of cisplatin and noise had a differential effect across frequencies (P < 0.001; ANOVA; F = 3.27, N = 47, df =
12). Additionally, only a difference of 10 dB or less was seen in the amount of high-frequency hearing loss between the cisplatin/85 dB SPL and
cisplatin/lOO dB SPL noise groups. Fig. 5 il- lustrates the amount of PTS for each of the cisplatin/noise groups in comparison to their noise-alone and cisplatin-alone control groups. A
statistical test of multiple comparison (Student- Newman-Keul (SNK)), no significant difference
(P > 0.05; SNK; N = 47, df = 40) was found in the amount of PTS among the cisplatin/70 dB SPL noise, the 70 dB SPL noise-alone and cispla- tin-alone groups (Fig. 5, Panel A), indicating that no interaction occurs between cisplatin and 70 dB SPL noise. The difference between the amount of
A CISPLATIN GROUP POST-TREATMENT MEAN
-lob 1 I 1 #lllLll I II#L,,l ,,,d 3 0.1 1 10 100
FREQUENCY (kHz)
B 500 Hz OBN GROU;)S
MEAN PERMANENT THRESHOLD SHI'T
50; L I , / 1’l-T.m e 100 dB SPL nlj
- 43 F
X 85 dB SPL c1 70 dL3 Si?L 1
r
g 3c;
20
- F
4 1
CISPLATIN + NOISE GROUPS C MEAN PERMANENT THRESHOLJ SHIFT
7 50 L e cis
; m CIS 4oE q CIS
-;
1,,, ,/I,,, --,--,
+ iO0 dB
b -10 4
I I ,,,A ,u,l L ,,,,I/ 1
0.1 1 10 100
FREQUENCY (kHz)
Fig. 4. Permanent threshold shift plotted as a function of frequency following exposure to cisplatin (Panel A), an octave
band of noise centered at 500 Hz at 70, 85 or 100 dB SPL
(Panel B) or the combination of cisplatin and noise (Panel C).
CIS/83=lE .5kHz OBN/COMBINATION
B MEfiN PERMWENT THRESHOLD SHIFT
::IS/lOOdB .SkWz OBN,‘CQMBINATTON
c MEAN PEFcMANENT THRESHOLD SHIFT
-10 t I I ,,,,,/I I / ,,I ,,,, , ,/ ,,/,/
0.1 1 10 100
FREQUENCY (kHz )
PTS for the cispiacin/M dB SPL noise group and its controls (Fig. 5. Panel B) was minimal at the low frequencies, but steadily increased as the CM
frequency increased so that 30-35 dB greater PTS existed in the cisplatin/noise group throughout the high frequencies. The pattern of PI’S among
the groups exposed Co cisplatin/la) dB SPL noise
and its controls (Fig. 5. Panel C) was similar to
that just described for the 85 dB SPL noise groups. The 15-20 dB PTS seen in the low frequencies of the interaction group was not statistically different f P == 0.05: SNK; N = 47, df = 40) from that of
the noise-alone control group, although it is greater than Chat incurred by the cisplatin-abne group.
However, the 30-45 dB PTS observed in the high frequencies of the cisplaCin/lOO dB SPL noise
group was greater (P < 0.05; SNK; ~1; --z 47. df = 40) than chat caused by either of the agents individually. The PTS data was analyzed using a three-way spiit plot with cisptatin and noise as the
between groups factors, and frequency as a rc- peated measure within groups. Results of the anal-
ysis (ANOVA with repeated measures) indicated significant main effects for all subjects receiving cisplatin or noise (P < 0.0001; ANOVA: F = 33.32. M = 47, df = 4), an interaction of cispla-
tin and noise (P c 0.001; ANOVA: F = 5.4. iii = 47, df = 2) and an interaction of frequency
by cisplatin by noise (P -c O.QoI: ANOVA: F == 3.27, N = 47, df = 12). A significant difference (P i U.001; ANOVA; F = 11.82, h’ = 47. df =
2) in the amount of PTS was found between the three groups given cisplatin/noise versus the three groups given noise-alone or the groups given cisplatin-alone.
The mean hair cell loss and mean PTS for the group which received cisplacin-alone are shown in
Fig. 6. A mean loss of lo-20% of OHCs was observed at the extreme basal end of the cochlea. Although very little PTS occurred ( -C 1 I dB PTS),
Fig. 5. Permanent threshold shin plotted as a function of frequency following exposure to cispladn, an octave band of noise centered at 500 Hz or the combiiation of cisplatin and noise The intensity of the noise was 70 dB SPL (Panel A). 85
dB SPL (Panel B) or 100 dB SPL (Panel C).
219
FREQUFNCY ( kHz ) FREQUENCY ( kHr )
0 i? 0 z 0,s I (1 s 0 10” 3, x ? 71 MGKG ClSPLATlN GROUP ,,“,
0 ?,I 40 64 80 I*1
% TOTAL DISTANCE FROM APEX
Fig. 6. Mean cochleogram depicting percentage of cell loss
plotted as a function of total distance from the apex and mean
F’TS plotted as a function of frequency for the group which
received cisplatin.
the frequencies at which even a minimal change in hearing occurred were found to be significantly related (P -e 0.01; Pearson’s r = 0.88; N = 7) with regions of outer hair cell loss. The mean hair cell loss and hearing loss for the group which received the 100 dB SPL noise-alone are shown in Fig. 7. The largest loss of OHCs (20-40%) oc- curred in the 0.3-4 kHz region of the cochlea. The
mean PTS (15-25 dB) as a function of frequency
(0.5-4 kHz) was found to be significantly related (P c 0.05; Pearson’s r = 0.79, N = 7) to the mean loss of OHCs. The mean cochleogram and
mean PTS of the 85 dB SPL and 70 dB SPL noise
FREQUENCY ( kHz )
0 io 4.0 Bo 80 loo
oic TOTAL DISTANCE FROM APEX
% TOTAL DISTANCE FROM APEX
Fig. 7. Mean cochleogram depicting percentage of cell loss
plotted as a function of total distance from the apex and mean
PTS plotted as a function of frequency for the group exposed
to a 100 dB SPL octave band of noise centered at 500 Hz.
groups (Fig. 8) showed less loss of hair cells than the group exposed to the 100 dB SPL noise (Fig.
7). A minimal amount of hair cell loss was noted in Fig. 8, which agrees with the mild to non-ex-
istent amount of PTS resulting from exposure to either the 85 dB SPL (Fig. 8, left) or 70 dB SPL (Fig. 8, right) octave band of noise centered at 500 Hz. The mean cochleogram and PTS for the group
which received cisplatin/lOO dB SPL noise is de- picted in Fig. 9. The cochleogram shows a 25-40s
mean loss of OHCs in the low frequency region (0.3-l kHz) of the cochlea. The degree of OHC loss increased with increasing distance from the
% TOTAL DISTANCE FROM APEX
Fig. 8. Mean cochleogram depicting percentage of cell loss plotted as a function of total distance from the apex and mean PTS plotted as a function of frequency for the group exposed to an octave band of noise centered at 500 Hz presented at either 85 dB SPL
(left) or 70 dB SPL (right).
WEQUENCY ( kHz I
‘% TOTAL DISTANCE FROM APEX
Fig. 9. Mean cochleogram depicting percentage of cell loss plotted as a function of total distance from the apex and mean
PTS plotti as a function of frequency for the group exposed
to the combination of cisplatin and a 100 dB SPL octave band
of noise centered at 500 Hz.
apex until it reached a plateau of 50-608 cell loss in the 75-10051; region (5-20 kHz) at the base of the cochlea. The mean PTS was significantly re- lated (P < 0.01; Pearson’s r = 0.89, iV = 7) to the mean OHC loss. The mean cochleogram for the cisplatin/85 dB SPL noise group (Fig. 10) was very similar in appearance to that of the cisplatin/lOO dB SPL noise group (Fig. 9) while that of the cisplatin/70 dB SPL noise group (Fig. 11) which incurred little or no F’TS was more similar to that of the cisplatin-alone group (Fig.
-40
-20
5% TOTAL DISTANCE FROM AI’EX
Fig. 10. Mean cochlqam depicting percentage of cell loss plotted as a function of total distance from the apex and mean W plotted as a function of frequency for the group exposed to the combination of cisplatin and an 85 dB SPL octave band
of noise centered at 500 Hz.
CHINCHILLA A”ERAGE OF 6 Tad Lcngh: 19.il mm
b 2’0 40 & i0 KU
‘3 TOTAL DISTANCE FROM APEX
Fig. 11. Mean cochleogram depicting percentage of cell loss plotted as a function of total distance from the apex and mean
PTS plotted as a function of frequency for the group exposed to the combination of cisplatin and a 70 dB SPL octave band
of noise centered at 500 Hz.
6). ~~tiple correlation analysis was performed using cell loss, test frequency and exposure group as predictors of hearing loss. The cell loss data was obtained by averaging the percent ceil loss by cell type along the length of the organ of Corti corresponding to the half-octave band centered around each test frequency for all animals in the group. The hearing loss data for each test frequency was obtained from the mean PTS audiogram. An overall significant relationship was found (P < 0.001; ANOVA; F = 217.51, N = 47, df = 45) between mean hearing loss and mean hair cell loss. The OHC, as well as the IHC, tosses were significantly related to degree of hear- ing loss. Thus, exposures which caused substantial amounts of hair cell damage also resulted in PTS.
Nephrotoxicity
Samples of urine and serum were collected from the groups of animals which received cisplatin- alone, the combination of cisplatin/lOO dB SPL noise and a control group of animals which re- ceived hydration-alone, with or without concur- rent exposure to the 100 dB SPL noise. The pur- pose of this was to determine if nephrotoxicity resulted from the administration of cisplatin, which in turn may have contributed to the cispla- tin/noise interaction. The urine and serum sam- ples were analyzed for change in the creatinine levels from pre- through post-exposure. Elevation
221
in the creatinine level did not occur during or after ad~~stration of the two cycles of cisplatin. No significant difference (0.1 -C P < 0.5 student t-test;
t.OS(Zm = 2.007) was found between the creatinine levels of the groups which received cisplatin-alone
or the combination of cisplatin/lOO dB SPL noise
and that of the hydrated control groups. This indicated that the cisplatin administration was
unlikely to have resulted in renal dysfunction.
Discussion
The results of this study demonstrate that cisplatin and noise can interact to increase the risk
of hair cell loss and hearing loss. Exposure to moderate (85 dB SPL) or high (100 dB SPL) levels of noise during cisplatin treatment si~fic~tly increased the degree of hearing loss and hair cell damage over and above that caused by either agent alone.
The threshold level with which noise interacts with cisplatin appears to be located between 70 to 85 dB SPL for the low frequency octave band of noise used in this study. Hawkins et al. (1975) noted that the threshold for interaction of kanamycin and noise in guinea pigs was ap- proximately 100 dB SPL for a ‘I-day noise ex-
posure. However, Brumett et al. (1988) found that a noise/kanamycin interaction occurred in guinea
pigs at noise levels that in themselves caused little or no permanent hearing loss. Thus, the present results are consistent with those of Brumett et al,
(1988). The magnitude of the cisplatin/noise interac-
tion appeared to be independent of the intensity level once the level of the noise reached or ex- ceeded 85 dB SPL, i.e., mean TTS, PTS and hair cell loss for the groups exposed to cisplatin/85 dB SPL noise and cisplatin/lOO dB SPL noise were
very similar. This is consistent with the results of Brown et al. (1978), who found that the amount of
cochlear microphonic ‘threshold shift’ reached an
asymptote as the dose of kanamycin was progres- sively increased during concurrent exposure to noise.
The rate at which the cisplatin/noise interac- tion developed and spread to other frequencies increased with the level of the noise exposure (Fig. 2). This suggests that for a given noise level, a
‘critical duration’ of noise exposure may be needed in order to induce the ~isplatin/noise interaction. Further research will be needed to determine the duration of the exposure necessary to cause an interaction with cisplatin for other exposure con-
ditions. Additionally, the cisplatin/noise interac-
tion may depend on the frequency of the noise as
well as noise level and duration. Since cisplatin initially causes a hearing loss at the higher fre-
quencies, one would expect the interaction effect to occur at lower noise levels and durations for
high frequency noise than for low frequency noise
exposures. As shown in Fig. 2, the cisplatin/noise interac-
tion was initially noted at the highest test frequen- cies and spread to the Ed-frequencies as the duration of the noise exposure increased. How-
ever, the amount of threshold shift in the low frequencies was constant whether or not the group had been exposed to the low frequency noise-alone or to the combination of noise and cisplatin.
Schweitzer et al. (1984) found that an interaction occurred between cisplatin and kanamycin in the high-frequency cochlear region. This is not surprising since that initial ototoxic effect of each of the drugs was observed at the most basal por- tion of the cochlea. In this study, a noise/drug
interaction occurred at the high frequencies even
though a low-frequency (500 Hz OBN) noise was coupled with the cisplatin ad~nistration. Simi-
larly, Ryan and Bone (1982) exposed c~nc~llas to a mid-frequency band of noise (1.4-5.6 kHz) and kanamycin, and found that the noise/drug interaction occurred at the high frequencies. How- ever, the interaction in the present study, only occurred when the low frequency noise was in- tense enough to produce a significant amount of threshold shift during the noise exposure at the high frequencies (Fig. 2). This suggests that for the interaction of noise and drug to occur, both agents must produce an effect in the same frequency
region.
Finally, it should be noted that the synergistic interaction of cisplatin and noise in this study occurred with a dose of cisplatin that simulated two chemotherapy treatments in humans. Thus the dose of cisplatin used in this study is one that could be realistically encountered clinically. Fur- thermore, the cisplatin, by itself, caused little or
222
no ototoxicity. Our results agree with the results of Komune and Snow (1981) as well as those of Brumett (1981). Both of these studies found that an interaction occurred between non-ototoxic do- ses of cisplatin and various diuretics which inhibit function of the loop of He&e.
The 85 dB SPL noise exposure level used in the present study is close to levels encountered in recreational or industrial settings; however, the duration of the exposure was quite long. Thus, such a noise exposure would probably not be encountered by a patient undergoing cisplatin chemotherapy. While the present study illustrates that a significant interaction can occur between cisplatin and noise, further work is needed to determine the acoustic conditions under which the interaction can occur. Particularly attention should be given to those acoustic conditions that are representative of those found in the workplace or recreation.
Since this study was conducted with an animal model, the results cannot be directly transferred to humans. However, the low noise intensity at which the chinchillas experienced an interaction of cisplatin and noise suggests that cancer patients receiving cisplatin chemotherapy who are concur- rently exposed to noise are at increased risk of incurring permanent hearing loss.
This research was supported in part by grants from the Deafness Research Foundation, NINCDS NS23894-03, and the Graduate Student Association Diamond Research Fund of SUNY at Buffalo. The authors which to thank Bristol- Meyers Company for the donation of Platinol and to acknowledge the assistance of Lynne I&n&i, Don Henderson, Meihn Poon, Nicholas Powers and Charles G. Wright.
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Holleh, A. (Ed.) (1986) The American Cancer Society Book:
