Elemental Mercury Vapour Toxicity, Treatment, and Prognosis After Acute, Intensive Exposure in Chloralkali Plant Workers. Part II: Hyperchloraemia and Genitourinary Symptoms
Bluhm, Julia A. Breyer, 1,2 1 Robert G. Bobbitt, 3 Larry 1,2 & Robert A. Branch 1,2 W. 3 Alastair Welch, J.J. Wood Renata E.
linical Pharmacology and 3 Medicine, C2 Departments of1 Psychiatry Vanderbilt University School 37232-6602, USA
of Medicine, Nashville, TN
to elemental mercury vapour is known to influence renal function; however, renal disease has not been consistently identified. Eleven men were evaluated for renal disease after acute, massive mercury poisoning. Significant hyperchloraemia was identified in this group of patients and a reversible renal tubular defect was suggested by low normal serum bicarbonate, a normal serum anion gap and a positive urinary anion gap. The only other evidence of renal dysfunction was transient, mild proteinuria in one of the 11patients. During this same time period, neuropsychological impairment was identified on a test of cognitive and visual-motor function, ’Trailmaking B’, in seven of the 11patients. Additionally, dysuria and ejaculatory pain occurred without evidence of urological disease. These complaints were more frequent in those patients with impairement on ’Trailmaking B’ suggesting a neurological basis for these symptoms. The findings of this study support earlier observations that the brain rather than the kidney is the critical target organ after elemental mercury vapour exposure.
Exposure severe
&dquo;
Introduction It is established that some chemical forms of mercury such as mercuric salts and organic I mercury are associated with renal dysfunction.’ After mercury vapour poisoning, however, renal effects are less well recognized. This may be due to the fact that renal dysfunction can be subtle, so that routine evaluation may not identify any
abnormality. A recent industrial incident exposed a group of chloralkali workers to elemental mercury. This unfortunate incident has provided an opportunity to evaluate renal function in a group of subjects who had mercury posioning and contrast the effects of mercury on the kidney with those on the CNS.
Method A group of 53 men were exposed to elemental mercury vapour while performing maintenance work on mercury cell lines at a chlorine manufacturing plant located in eastern Tennessee. The plant uses mercury as an electrolytic catalyst. The details of the elemental mercury exposure
described in Part L2 There was a delay of between 19 and 36 d after the exposure before the men were evaluated at this institution. Eleven of the men with higher urine mercury levels underwent a longer and more intensive follow-up, and they are the subjects of this study. Patients had serial measurements of blood mercury, serum sodium, potassium, chloride, are
bicarbonate, creatinine, blood
urea
nitrogen,
and urine mercury, creatinine and urinalysis between day 19 and day 570 after the mercury exposure. Urine protein electrophoresis and serum creatine phosphokinase were measured only at the time of initial evluation. Two of the patients had arterial blood gas measurements including blood pH. Sodium, chloride, and potassium was measured in urine collected over 24 h on days (mean) 82, 85, 87, and 92 after mercury exposure.
Patients received a 2-week course of chelating therapy with either 2,3-dimercaptosuccinic acid (DMSA) or N-acetyl-D,L-penicillamine (NAP) after day 29, and again for 4 d between days 84 (mean) and 88.
Correspondence: Renata E. Bluhm.
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
212
Assay of total mercury was done on whole blood collected into a heparin container and on urine which was collected into plastic containers using a method previously described. 2,3 Urine mercury. data is represented as mercury mcg / d-’. Serum sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen and urine sodium, potassium and chloride were measured by standard automated techniques. The normal range was determined by institutional standards. The urinary anion gap was determined by
calculation:4,5
~(SOdlllmurine + POtasSlLlmurine) - ChlOrideurine~ Since the serum and urine chloride was measured colorimetrically using an automated a method that thiocyanate employs mercurimetric titration, the possibility that the presence of mercury in blood may interfere with the assay of chloride was considered. Thus, several control serum samples obtained from normal, non-exposed subjects were measured for chloride before and after the addition of elemental mercury (100 ng ml - ). There was no change in the amount of chloride measured. Although the analysis of chloride employs a mercuric ion, the serum chloride is proportionally so much higher in concentration that it is not affected by the amount of mercury in the patient’s serum. In fact, significant mercury in the patients’ serum should, if anything, have the effect of producing spuriously low serum chloride values when using this chloride analysis technique.’ Hyperlipidaemia, which can spuriously elevate serum7 chloride was not present in any of the patients? Serum bromide can also cause a spurious hyperchloraemia; however, no patient had a history of bromide ingestion.’ Normal values for serum chloride were determined from clinical laboratory control data of the time period during which the patients’ serum was analysed (102.9
meql~±1.6). Creatinine was measured in urine by the Technicon Auto Analyser using sodium picrate as a colorimetric reagent. Urine pH was measured using an Ames@ colorimetric method. Tests of cognitive and visual-motor ability, including ’Trailmaking B’, were administered on mean day 62 ± 21 after mercury exposure as described in Part L2 ’Trailmaking B’ is one of the most sensitive measures in the Halstead-Reitan battery and assesses visual attention, visualmotor speed and ability to sequence and shift mental set. A test time of 91 s or less has been described as normal for population controls.99
the group means for these tests were all within normal except for the serum chloride (Table 1). Of the total of 124 serum chloride tests for the 11 patients, 100 of these tests (80.6%) were noted to be greater than 105 meq 1 -1 (95105 mgl -’ normal range). Urinary creatinine clearance was normal in all patients ( 122 ± 26 ml min -’, group mean ± s.d.). When measured on day 19 after mercury exposure, urinalysis was normal in all but one of the patients in whom a modest proteinuria (0.21 g protein g-’ creatinine) was noted which resolved over the next several weeks; this patient had a urinary mercury excretion quantitatively similar to the other 10 patients (Table 2). Urological symptoms of ejaculatory pain were reported by seven of the 11 patients, who stated that pain was so severe they abstained from sexual intercourse. Dysuria also occurred. Their urological exam was without signs of prostatitis, epididymitis or urethral discharge. There was no evidence of urinary tract infection on urinalysis. Neuropsychological function was assessed using the ’Trailmaking B’ test because of the prominent CNS symptoms which were reported by the patients. Headache, irritability, increased temper, mood changes and decreased sociability were quantitated with the ’Symptom Check List 90 - Revised’, a test of subjective psychological distress for which these patients had markedly abnormal scores as described in Part 1.~ Table 2 relates symptoms with other toxicological parameters and hyperchloraemia. Ten of the 11I patients had a mean serum chloride above the normal range, although all patients had hyperchloraemia at some time during their evaluation. It is noted that patient #1, who’s mean serum chloride was high normal, also was within the normal range in his performance of
’Trailmaking B’. Dysuria and ejaculatory pain occurred in the group of men with impairment on ’Trailmaking B’. Blood and urine mercury were measured at variable times over a total of 570 d. Figure 1 Table 1 Serum
chemistry after mercury
exposure.
Results Evaluation of the
serum
chemistry indicates that
Mean of group from serial measurements performed within days 19-145 after mercury exposure.
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
213
Table 2
Toxicological parameters after mercury
exposure.
aEarliest measurement available for patient
bMean for patient of serial
measurements
’Obtained from earliest recorded history d + performance time longer than 91 s, - less than 91
s
tUnknown shows the time course for the group for blood and urine mercury and serum chloride. It can be seen that 570 d after mercury exposure, when
urinary
mercury
hyperchloraemia was
was
not
measurable,
resolved in all
patients.
patients, the serum anion gap was approximately 10. The average ratio of sodium to chloride was 1.29. HyperIn the
normal,
at
chloraemia was associated with a low normal serum bicarbonate (25.9 ± 3.8 mean ± s.d.), but 13% of the serum bicarbonate measurements were below normal (23-30 mmol 1-’ normal range). Arterial blood pH was normal, 7.41, 7.45, (7.35-7.45 normal range) in the two patients who had arterial blood pH measured at days 19 and 36, respectively, after the mercury exposure. The arterial PC02 in these two patients was also within the normal range (42, 39 mmHg with 35-45 mmHg normal range) and did not reveal any underlying respiratory alkalosis. Urinary pH was normal. The analysis of the urinary anion gap in these patients revealed a positive urinary anion gap of 39.11 ± 33.06 (mean±s.d.) suggesting low ammonium excretion.
Discussion
Although there are high concentrations of mercury in the kidney after elemental mercury exposure,
severe
renal disease has not been consis-
tently reported. 1,10o Proteinuria and the nephrotic syndrome have been reported in some patients. 11,12 In asymptomatic workers exposed occupationally to elemental mercury mild pro-3 teinuria 1 Time course of group mean blood mercury, urine mercury excretion mgc d -’ and serum chloride up to 570 d after mercury exposure.
Figure
was
demonstrated in
some
workers.’
Proteinuria, thus, is not a uniform finding in all patients after elemental mercury exposure and was found transiently in only one patient in the present study. It has been suggested that
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
214
glomerular disease after elemental mercury may4 be of immunological or inflammatory origin’ and this may explain the variability in the occurrence of proteinuria among individuals exposed to elemental mercury. Reduction in creatinine clearance has also been reported after elemental mercury exposure. IS, 16 Despite massive mercury exposure suflicient to induce neurotoxicity and elevated concentrations of mercury in blood and urine, creatinine clearance was not impaired during the study period in the patients described in this report. In the present study, however, hyperchloraemia with a low normal bicarbonate was noted in all patients. Hyperchloraemia can occur as a result of dehydration or a change in the the acid-base balance. In the case of dehydration, the serum sodium will change in proportion to the change in chloride maintaining the sodium-chloride ratio at 1.4. Since the sodium-chloride ratio was decreased to 1.29 in the presence of a normal serum sodium, this suggests that the hyperchloraemia seen in these patients was not due to dehydration, but rather to a change in acid-base balance. Heperchloraemia in the patients described migh~have been due to either a chronic respiratory alk4losis or a non-serum anion gap metabolic acidosis. These patients, however, had no evidence of any chronic respiratory process and, in the patients in whom arterial blood gases were performed, no respiratory alkalosis was found. The rate of ammonium (NH4) excretion in the urine provides an excellent measurement of the 7 kidney’s ability to respond to an acid load. 1 Direct measurements of the NH4 excretion in the urine are difficult to perform, but urinary NH4 excretion can be estimated through the use of the urinary anion gap. Ammonium is normally excreted with chloride. When the urinary anion gap equals zero, the NH4 excretion is about 80 mmoll - 1. As the NH4 excretion increases, the urinary anion gap has an increasingly negative value. A positive urinary anion gap indicates little urinary ammonium. The positive urinary anion gap identified in these patients makes non-renal losses of bicarbonate, such as occurs with diarrhoea, an unlikely explanation for the hyperchloraemia. In the presence of a high serum chloride, low normal serum bicarbonate, normal serum anion gap and positive urinary anion gap (indicating decreased NH4 excretion by the kidney) a renal tubular defect in bicarbonate handling is suggested and hyperchloraemia in these mercury-exposed patients was, therefore, most likely due to a subtle defect in urinary acid excretion. Despite wide variability in each patient’s urinary mercury excretion, all 11 patients had hyperchloraemia.
It is thought that during the acute elemental mercury vapour exposure of these patients, the kidney mercury levels may have reached a level which was sufficient to cause tubular damge. The mercuric salts and organomercurials are well known to produce renal tubular effects.&dquo;8
Tubular damage after accidental inorganic mercuric salt exposure has also been reported.’9 Renal tubular abnormalities have, however, not been previously reported after elemental mercury
toxicity.
Urinary
rr-acetyl-(3-gluco-
enzyme in urine that may be a marker for tubular toxicity, has been studied in individuals after elemental mercury exposure and was found to be increased when urine mercury concentrations were above 500
saminidase,
a
lysosomal
nmol 1-’ .20 It has been suggested that elemental mercury is rapidly oxidized in the blood, heart and brain.3 Thus, it is possible that after oxidation, elemental mercury may act as mercuric or divalent mercury and thus be identical to the chemical form that occurs after dissociation of mercuric salts.2’ These dissociated mercuric ions could then produce renal tubular damage similar to that seen after ingestion of mercuric chloride or the mercurial diuretics. A renal tubular defect may become clinically significant if patients excrete or fail to regenerate lost bicarbonate such as in sepsis or diarrhoea. Thus, after mercury exposure, the presence of a tubular defect manifested only subtly by hyperchloraemia should be considered in the management of the patient. Additionally, this may be another cause of hyperchloraemia that has not previously been recognized. If the history includes occupational exposure to mercury, other evidence for mercury toxicity should be sought. Further investigation of the ability of mercuryexposed patients with this tubular defect to handle an acid load are necessary to clarify the potential clinical significance of this abnormal-
ity. The influence of mercury on regional organ appears to be dependent on the molecular nature of the mercury ingested. Following exposure to mercuric salts, the kidney, particularly proximal tubular epithelial cells, is the initial and prime site of toxicity, with neu-
toxicity
rotoxicity only occurring at higher exposure.’I Complexing of mercury in an organomercurial results in approximate equal organ sensitivity for the kidney and the brain. In contrast, exposure to elemental mercury results in initial and prime
neurotoxicity. 10 The observations in the cohort of patients in the present study confirms that in the latter situation only subtle changes in tubular function occur at a time that there was clear evidence of neurotoxicity.
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215
A novel observation in this cohort of subjects exposed to elemental mercury was the frequency and severity of ejaculatory pain. This symptom has not, to our knowledge, been reported. It was, however, alluded to by Taylor in his description of a patient with elemental mercury toxicity as ’pain in the loins’ associated with ’great weak-
and want of nervous power’.22 The cause for the pain is unknown. In the absence of local urological abnormalities, and in the presence of other neurological signs and symptoms, it is ness
reasonable to think that it was a consequence of a local peripheral neuropathy. This once again indicates that the nervous system is the prime target for elemental mercury toxicity.
Acknowledgements This work was supported, in part, by US Public Health Service Grant GM 31304 and WIH General Clinical Research Center Grant RR 0095.
References Clinical toxicology of commercial products eds Gosselin RE, Smith RP, Hodge HC & Braddock JE, 5th ed Baltimore: Williams and Wilkins, 1984. 2 Bluhm RE, Bobbitt RG, Welch LW et al. Elemental mercury vapor toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers: Part I: History, neuropsychological findings and chelator effects 1992; 11: 201-10. 3 Clarkson TW, Greenwood MR & Magos L. Atomic absorption determination of total, inorganic and organic mercury in biological fluids. IN: Clinical chemistry and Chemical Toxicology of Metals, ed Brown 55, pp 201-4. Amsterdam: Elsevier Science Publishers, 1977. 4 Goldstein MB, Bear, Richardson RMS, Marsden PA & Halperin ML. The urine anion gap: a clinically useful index of ammonium excretion. American Journal of Medical Science 1986; 292: 198-202. 5 Wong AK & Cutler RE. Modem Urinaylysis, Part 2: the use of urinary electrolytes. Dialysis and Transplantation
1 Mercury.
6
1990; Jan: 38-47. Young DS, Pestaner LC & Gibberman V. Effects of drugs on clinical laboratory tests. Clinical Chemistry 1975; 21: 1D-432D.
7 Graber ML, Quigg RJ, Stempsey, WE & Weis S. Spurious
hyperchloremia and decreased hyperlipidemia. Annals of Internal
anion in gap Medicine 1983; 98:
607-9.
8 Kan K, Satowa S, Takeuchi I, Saruta T & Kano S. Unusual apparent hyperchloremia induced by long-term abuse of
bromide-containing drugs. International Journal of Clinical Pharmacology, Therapy and Toxicology 1986; 24: 399-402. 9
Yeudall, LT, Reddon JR, Gill DM &
Stefanyk WO. for the Halstead Reitan Neuropsychological test stratified by age and sex. Journal of Clinical Psychology 1987: 43: 346-67. Stokinger HE. The Metals. In: Patty’s Industrial Hygiene and Toxicology, Clayton GD & Clayton FE, pp 1778-91. New York: John Wiley and Sons, 1981. Jaffe KM, Shurtleff DB & Robertson WO. Survival after Normative
10
11
data
acute mercury vapor poisoning. American Journal of Diseases of Children 1983; 137: 749-51. 12 McNeil NI, Olver RE, Issler HC & Wrong OM. Domestic metallic mercury poisoning. Lancet 1984; 1: 269-71. 13 Joselow MM & Goldwater LJ. Absorption and excretion of mercury in man. Archives of Environmental Health 1967; 15: 155-9. 14 Tubbs RR, Gephardt GN, McMahon JT et al. Membranous glomerulonephritis associated with industrial mercury exposure. American Journal of Clinical Pathology 1982; 77: 409-13. 15 Lien DC, Todoruk DN, Hasmukhal RR, Cook DA & Herbert FA. Accidental inhalation of mercury vapour. respiratory and toxicologic consequences. Canadian Medical Association Journal 1983; 129: 591-5. 16 Buchet JP, Roels H, Bernar A & Lauwerys R. Assessment of renal function of workers exposed to inorganic lead, cadmium, or mercury vapor. Journal of Occupational Medicine 1980; 22: 741-50. 17 Halperion ML, Goldstein MB, Richardson RMS & Stinebaugh BJ. Distal renal tubular acidosis syndromes: a pathophysiological approach. American Journal of Nephrology 1985, 5: 1-8. 18 Clarkson TW & Vostal JJ. Mercurials, mercuric ion and sodium transport. In Modern Diuretic Therapy in the Treatment of Cardiovascular and Renal disease, ed Lant AF & Wilson GM, pp 229-40. Amsterdam: Excerpta, 1973. 19 Husband P & McKeller WJD. Infantile renal tubular acidosis due to mercury poisoning. Archives of Disease in Childhood 1970: 45: 264-8. 20 Piikivi L & Ruokonen A. Renal function and long-term low mercury vapor exposure. Archives of Environmental Health 1989; 44: 146-9. 21 Clarkson TW, Hursch JB, Sager PR & Syversen TLM. Mercury. In: Biological Monitoring of Toxic Metals, eds Clarkson TW, Friberg L, Nordberg GF, Sager PR, pp 199-245. New York: Plenum Press, 1988. 22 Anonymous. Clinical Toxicology 1991; 29: 151-64.
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
Bluhm, Julia A. Breyer, 1,2 1 Robert G. Bobbitt, 3 Larry 1,2 & Robert A. Branch 1,2 W. 3 Alastair Welch, J.J. Wood Renata E.
linical Pharmacology and 3 Medicine, C2 Departments of1 Psychiatry Vanderbilt University School 37232-6602, USA
of Medicine, Nashville, TN
to elemental mercury vapour is known to influence renal function; however, renal disease has not been consistently identified. Eleven men were evaluated for renal disease after acute, massive mercury poisoning. Significant hyperchloraemia was identified in this group of patients and a reversible renal tubular defect was suggested by low normal serum bicarbonate, a normal serum anion gap and a positive urinary anion gap. The only other evidence of renal dysfunction was transient, mild proteinuria in one of the 11patients. During this same time period, neuropsychological impairment was identified on a test of cognitive and visual-motor function, ’Trailmaking B’, in seven of the 11patients. Additionally, dysuria and ejaculatory pain occurred without evidence of urological disease. These complaints were more frequent in those patients with impairement on ’Trailmaking B’ suggesting a neurological basis for these symptoms. The findings of this study support earlier observations that the brain rather than the kidney is the critical target organ after elemental mercury vapour exposure.
Exposure severe
&dquo;
Introduction It is established that some chemical forms of mercury such as mercuric salts and organic I mercury are associated with renal dysfunction.’ After mercury vapour poisoning, however, renal effects are less well recognized. This may be due to the fact that renal dysfunction can be subtle, so that routine evaluation may not identify any
abnormality. A recent industrial incident exposed a group of chloralkali workers to elemental mercury. This unfortunate incident has provided an opportunity to evaluate renal function in a group of subjects who had mercury posioning and contrast the effects of mercury on the kidney with those on the CNS.
Method A group of 53 men were exposed to elemental mercury vapour while performing maintenance work on mercury cell lines at a chlorine manufacturing plant located in eastern Tennessee. The plant uses mercury as an electrolytic catalyst. The details of the elemental mercury exposure
described in Part L2 There was a delay of between 19 and 36 d after the exposure before the men were evaluated at this institution. Eleven of the men with higher urine mercury levels underwent a longer and more intensive follow-up, and they are the subjects of this study. Patients had serial measurements of blood mercury, serum sodium, potassium, chloride, are
bicarbonate, creatinine, blood
urea
nitrogen,
and urine mercury, creatinine and urinalysis between day 19 and day 570 after the mercury exposure. Urine protein electrophoresis and serum creatine phosphokinase were measured only at the time of initial evluation. Two of the patients had arterial blood gas measurements including blood pH. Sodium, chloride, and potassium was measured in urine collected over 24 h on days (mean) 82, 85, 87, and 92 after mercury exposure.
Patients received a 2-week course of chelating therapy with either 2,3-dimercaptosuccinic acid (DMSA) or N-acetyl-D,L-penicillamine (NAP) after day 29, and again for 4 d between days 84 (mean) and 88.
Correspondence: Renata E. Bluhm.
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
212
Assay of total mercury was done on whole blood collected into a heparin container and on urine which was collected into plastic containers using a method previously described. 2,3 Urine mercury. data is represented as mercury mcg / d-’. Serum sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen and urine sodium, potassium and chloride were measured by standard automated techniques. The normal range was determined by institutional standards. The urinary anion gap was determined by
calculation:4,5
~(SOdlllmurine + POtasSlLlmurine) - ChlOrideurine~ Since the serum and urine chloride was measured colorimetrically using an automated a method that thiocyanate employs mercurimetric titration, the possibility that the presence of mercury in blood may interfere with the assay of chloride was considered. Thus, several control serum samples obtained from normal, non-exposed subjects were measured for chloride before and after the addition of elemental mercury (100 ng ml - ). There was no change in the amount of chloride measured. Although the analysis of chloride employs a mercuric ion, the serum chloride is proportionally so much higher in concentration that it is not affected by the amount of mercury in the patient’s serum. In fact, significant mercury in the patients’ serum should, if anything, have the effect of producing spuriously low serum chloride values when using this chloride analysis technique.’ Hyperlipidaemia, which can spuriously elevate serum7 chloride was not present in any of the patients? Serum bromide can also cause a spurious hyperchloraemia; however, no patient had a history of bromide ingestion.’ Normal values for serum chloride were determined from clinical laboratory control data of the time period during which the patients’ serum was analysed (102.9
meql~±1.6). Creatinine was measured in urine by the Technicon Auto Analyser using sodium picrate as a colorimetric reagent. Urine pH was measured using an Ames@ colorimetric method. Tests of cognitive and visual-motor ability, including ’Trailmaking B’, were administered on mean day 62 ± 21 after mercury exposure as described in Part L2 ’Trailmaking B’ is one of the most sensitive measures in the Halstead-Reitan battery and assesses visual attention, visualmotor speed and ability to sequence and shift mental set. A test time of 91 s or less has been described as normal for population controls.99
the group means for these tests were all within normal except for the serum chloride (Table 1). Of the total of 124 serum chloride tests for the 11 patients, 100 of these tests (80.6%) were noted to be greater than 105 meq 1 -1 (95105 mgl -’ normal range). Urinary creatinine clearance was normal in all patients ( 122 ± 26 ml min -’, group mean ± s.d.). When measured on day 19 after mercury exposure, urinalysis was normal in all but one of the patients in whom a modest proteinuria (0.21 g protein g-’ creatinine) was noted which resolved over the next several weeks; this patient had a urinary mercury excretion quantitatively similar to the other 10 patients (Table 2). Urological symptoms of ejaculatory pain were reported by seven of the 11 patients, who stated that pain was so severe they abstained from sexual intercourse. Dysuria also occurred. Their urological exam was without signs of prostatitis, epididymitis or urethral discharge. There was no evidence of urinary tract infection on urinalysis. Neuropsychological function was assessed using the ’Trailmaking B’ test because of the prominent CNS symptoms which were reported by the patients. Headache, irritability, increased temper, mood changes and decreased sociability were quantitated with the ’Symptom Check List 90 - Revised’, a test of subjective psychological distress for which these patients had markedly abnormal scores as described in Part 1.~ Table 2 relates symptoms with other toxicological parameters and hyperchloraemia. Ten of the 11I patients had a mean serum chloride above the normal range, although all patients had hyperchloraemia at some time during their evaluation. It is noted that patient #1, who’s mean serum chloride was high normal, also was within the normal range in his performance of
’Trailmaking B’. Dysuria and ejaculatory pain occurred in the group of men with impairment on ’Trailmaking B’. Blood and urine mercury were measured at variable times over a total of 570 d. Figure 1 Table 1 Serum
chemistry after mercury
exposure.
Results Evaluation of the
serum
chemistry indicates that
Mean of group from serial measurements performed within days 19-145 after mercury exposure.
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
213
Table 2
Toxicological parameters after mercury
exposure.
aEarliest measurement available for patient
bMean for patient of serial
measurements
’Obtained from earliest recorded history d + performance time longer than 91 s, - less than 91
s
tUnknown shows the time course for the group for blood and urine mercury and serum chloride. It can be seen that 570 d after mercury exposure, when
urinary
mercury
hyperchloraemia was
was
not
measurable,
resolved in all
patients.
patients, the serum anion gap was approximately 10. The average ratio of sodium to chloride was 1.29. HyperIn the
normal,
at
chloraemia was associated with a low normal serum bicarbonate (25.9 ± 3.8 mean ± s.d.), but 13% of the serum bicarbonate measurements were below normal (23-30 mmol 1-’ normal range). Arterial blood pH was normal, 7.41, 7.45, (7.35-7.45 normal range) in the two patients who had arterial blood pH measured at days 19 and 36, respectively, after the mercury exposure. The arterial PC02 in these two patients was also within the normal range (42, 39 mmHg with 35-45 mmHg normal range) and did not reveal any underlying respiratory alkalosis. Urinary pH was normal. The analysis of the urinary anion gap in these patients revealed a positive urinary anion gap of 39.11 ± 33.06 (mean±s.d.) suggesting low ammonium excretion.
Discussion
Although there are high concentrations of mercury in the kidney after elemental mercury exposure,
severe
renal disease has not been consis-
tently reported. 1,10o Proteinuria and the nephrotic syndrome have been reported in some patients. 11,12 In asymptomatic workers exposed occupationally to elemental mercury mild pro-3 teinuria 1 Time course of group mean blood mercury, urine mercury excretion mgc d -’ and serum chloride up to 570 d after mercury exposure.
Figure
was
demonstrated in
some
workers.’
Proteinuria, thus, is not a uniform finding in all patients after elemental mercury exposure and was found transiently in only one patient in the present study. It has been suggested that
Downloaded from het.sagepub.com at UNIVERSITY OF SASKATCHEWAN LIBRARY on March 17, 2015
214
glomerular disease after elemental mercury may4 be of immunological or inflammatory origin’ and this may explain the variability in the occurrence of proteinuria among individuals exposed to elemental mercury. Reduction in creatinine clearance has also been reported after elemental mercury exposure. IS, 16 Despite massive mercury exposure suflicient to induce neurotoxicity and elevated concentrations of mercury in blood and urine, creatinine clearance was not impaired during the study period in the patients described in this report. In the present study, however, hyperchloraemia with a low normal bicarbonate was noted in all patients. Hyperchloraemia can occur as a result of dehydration or a change in the the acid-base balance. In the case of dehydration, the serum sodium will change in proportion to the change in chloride maintaining the sodium-chloride ratio at 1.4. Since the sodium-chloride ratio was decreased to 1.29 in the presence of a normal serum sodium, this suggests that the hyperchloraemia seen in these patients was not due to dehydration, but rather to a change in acid-base balance. Heperchloraemia in the patients described migh~have been due to either a chronic respiratory alk4losis or a non-serum anion gap metabolic acidosis. These patients, however, had no evidence of any chronic respiratory process and, in the patients in whom arterial blood gases were performed, no respiratory alkalosis was found. The rate of ammonium (NH4) excretion in the urine provides an excellent measurement of the 7 kidney’s ability to respond to an acid load. 1 Direct measurements of the NH4 excretion in the urine are difficult to perform, but urinary NH4 excretion can be estimated through the use of the urinary anion gap. Ammonium is normally excreted with chloride. When the urinary anion gap equals zero, the NH4 excretion is about 80 mmoll - 1. As the NH4 excretion increases, the urinary anion gap has an increasingly negative value. A positive urinary anion gap indicates little urinary ammonium. The positive urinary anion gap identified in these patients makes non-renal losses of bicarbonate, such as occurs with diarrhoea, an unlikely explanation for the hyperchloraemia. In the presence of a high serum chloride, low normal serum bicarbonate, normal serum anion gap and positive urinary anion gap (indicating decreased NH4 excretion by the kidney) a renal tubular defect in bicarbonate handling is suggested and hyperchloraemia in these mercury-exposed patients was, therefore, most likely due to a subtle defect in urinary acid excretion. Despite wide variability in each patient’s urinary mercury excretion, all 11 patients had hyperchloraemia.
It is thought that during the acute elemental mercury vapour exposure of these patients, the kidney mercury levels may have reached a level which was sufficient to cause tubular damge. The mercuric salts and organomercurials are well known to produce renal tubular effects.&dquo;8
Tubular damage after accidental inorganic mercuric salt exposure has also been reported.’9 Renal tubular abnormalities have, however, not been previously reported after elemental mercury
toxicity.
Urinary
rr-acetyl-(3-gluco-
enzyme in urine that may be a marker for tubular toxicity, has been studied in individuals after elemental mercury exposure and was found to be increased when urine mercury concentrations were above 500
saminidase,
a
lysosomal
nmol 1-’ .20 It has been suggested that elemental mercury is rapidly oxidized in the blood, heart and brain.3 Thus, it is possible that after oxidation, elemental mercury may act as mercuric or divalent mercury and thus be identical to the chemical form that occurs after dissociation of mercuric salts.2’ These dissociated mercuric ions could then produce renal tubular damage similar to that seen after ingestion of mercuric chloride or the mercurial diuretics. A renal tubular defect may become clinically significant if patients excrete or fail to regenerate lost bicarbonate such as in sepsis or diarrhoea. Thus, after mercury exposure, the presence of a tubular defect manifested only subtly by hyperchloraemia should be considered in the management of the patient. Additionally, this may be another cause of hyperchloraemia that has not previously been recognized. If the history includes occupational exposure to mercury, other evidence for mercury toxicity should be sought. Further investigation of the ability of mercuryexposed patients with this tubular defect to handle an acid load are necessary to clarify the potential clinical significance of this abnormal-
ity. The influence of mercury on regional organ appears to be dependent on the molecular nature of the mercury ingested. Following exposure to mercuric salts, the kidney, particularly proximal tubular epithelial cells, is the initial and prime site of toxicity, with neu-
toxicity
rotoxicity only occurring at higher exposure.’I Complexing of mercury in an organomercurial results in approximate equal organ sensitivity for the kidney and the brain. In contrast, exposure to elemental mercury results in initial and prime
neurotoxicity. 10 The observations in the cohort of patients in the present study confirms that in the latter situation only subtle changes in tubular function occur at a time that there was clear evidence of neurotoxicity.
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A novel observation in this cohort of subjects exposed to elemental mercury was the frequency and severity of ejaculatory pain. This symptom has not, to our knowledge, been reported. It was, however, alluded to by Taylor in his description of a patient with elemental mercury toxicity as ’pain in the loins’ associated with ’great weak-
and want of nervous power’.22 The cause for the pain is unknown. In the absence of local urological abnormalities, and in the presence of other neurological signs and symptoms, it is ness
reasonable to think that it was a consequence of a local peripheral neuropathy. This once again indicates that the nervous system is the prime target for elemental mercury toxicity.
Acknowledgements This work was supported, in part, by US Public Health Service Grant GM 31304 and WIH General Clinical Research Center Grant RR 0095.
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