Immunological effects of occupational exposure tometallic mercury in the population of T-cells andNK-cells†

Paulin Moszczynski, Jan Rutowski*, Stefan S /lowinski, S/lawomir BemInternational Institute of Universalistic Medicine in Warsaw, Department in Tarnow, 178 ALwowska Street, 33-100 Tarnow, Poland

This paper presents a study of the counts of lymphocytes,(CD3+)T-cells, (CD4+)T-helper and (CD8+)T-suppressorand (CD16+)NK-cells in the peripheral blood of 101 maleswith a history of occupational exposure to metallicmercury vapours (Hg0) and in 36 males without thisexposure. These workers were divided depending on theduration of exposure: 37 males with a short-term historyof exposure to Hg0 (up to 10 years) and 64 males with ahistory of long-term exposure (10 to 37 years). For thedetermination of T-cell populations monoclonal antibodieswere used in indirect immunofluorescence tests. The timeweighted average of mercury concentrations in air was0.028 mg m23. Mercury concentration in the urine of theexposed subjects ranged from 20–260 mg dm23, and inblood it was from 4 to 72 mg dm23. Stimulation of theT-cell line was noted as evidenced by increased numbersof (CD3+)T-cells, (CD4+)T-helper and(CD8+)T-suppressor cells in the workers with < 10 or> 10 years’ exposure to Hg0. Lower increase count of(CD3+)T-cells and (CD4+)T-helper cells than(CD8+)T-suppressor cells was the cause of decreasedvalues in the (CD3+)T/(CD8+)T-suppressor ratio and(CD4+)T-helper/(CD8+)T-suppressor ratio in the workerswith < 10 or > 10 years’ of exposure. Moreover, nochanges were observed in the T-cell populations betweenworkers with < 10 and those with > 10 years’ exposure. Inaddition, statistical analysis of the effects of age andduration of exposure to Hg0 on the studied immunologicalparameters indicates that exposure duration may affectsome of the values. These quantitative changes of T-cellpopulation as well as changes of the(CD3+)T/(CD8+)T-suppressor and (CD4+)T-helper/(CD8+)T-suppressor ratio have been proposed asimmunological indicators of exposure to Hg0, which canbe used for monitoring and to explain the origin ofautoimmunity disorders induced by metallic mercury.

Keywords: Metallic mercury vapours; occupational exposure;immunity; lymphocytes; (CD3+)T-cells; (CD4+)T-helper;(CD8+)T-suppressor; (CD16+)NK-cells; monoclonalantibodies

The immunotoxicology of mercury compounds, especiallymetallic mercury, is important clinically. Some heavy metalssuch as mercury and lead can enhance humoral immunity,mainly antibody production with autoimmunity responses,suppress cell-mediated immunity and interfere with hostdefence against pathogens by direct action on cells of theimmune system. The two major cell types responsible for theregulation of cell-mediated immunity are macrophages and(CD4+)T-helper (Th) cells of the Th1 subset. The Th1 subset

produces IL-2 and IFN-g upon activation: whereas, the Th2subset produces IL-4, IL-5, IL-6 and IL-10 which preferentiallyenhance humoral immunity (Lawrence,1 Zelikoff et al.2).Immunoregulatory networks are also based on a delicatebalance between T-helper and T-suppressor cells.

The effect of mercury on the immune system has been studiedmainly in laboratory animals, and it has been found thatmethylmercury inhibits both humoral and cell-mediated im-mune reactions. After administration to mice, mercury causes atransient atrophy of thymus cortex and lymph follicles(Hirokawa and Hayashi3), and reduces the number of NK-cells(Ilback4) and DNA synthesis of mitogen-stimulated lymphocytecultures (Nakatsuru et al.5). HgCl2 stimulates DNA synthesis inlymphocytes and thymocytes (Nordlind6) and acts as a T-celldependent polyclonal activator of B-cells (Esnault et al.,7Hultman and Enestrom,8 Pusey et al.9). Mercury can primarilyactivate murine T lymphocytes to transformation and prolifera-tion in vitro. In vivo administration of HgCl2 causes au-toimmune manifestations in rats and mice (Jiang and Moller.10)Susceptible Brown–Norway (BN) rats exhibit a (CD4+)T-cell-dependent polyclonal activation of B cells, the total number ofT-cells increasing very rapidly but in contrast, Lewis (LEW)rats are resistant and develop an immunosuppression mediatedby (CD8+)T-cells recruited by (CD4+)T-cells (Fillion et al.11)HgCl2 in certain concentrations also acts as a stimulator ofhuman lymphocytes in cultures, increasing the production oflymphokines and DNA synthesis (Nordlind,6 Holst and Nor-dlind,12 Perlingeiro and Queiroz.13) HgCl2 (up to 1000 ng) andmethylmercury (up to 100 ng) impairs mitogen stimulatedhuman lymphocyte T proliferation, impairs their ability tosynthesise interleukin-1 (IL-1) and damages IL-1 and trans-ferrin receptor (Shenker et al.14)

Little data is available on the effects of mercury vapours onthe human immune system (Izdebska-Szymona and Kopec-Szlezak,15 Lawrence,1 Moszczynski et al.,16,17 Zelikoff et al.2),especially during long occupational exposure. Mercury hasbeen shown to affect lymphocyte function and to modulateimmune reactivity (Bigazzi,18 Michaelson et al.19) The effectsof exposure to mercury have been linked to autoimmunedisorders, mainly types II and III allergic reactions, either byacting as a hapten or altering the antigenicity of cellular proteins(Perlingeiro and Queiroz,13 Zelikoff et al.,2 Queiroz et al.20)Low mercury vapour concentrations during occupational expo-sure can stimulate immunity. In 41 men exposed to Hg0 vapourselevated levels of serum immunoglobulins IgA, IgM and serumacute phase proteins were observed (Bencko et al.21)

The influence of low exposure to inorganic mercury on the T-cell population was examinated only in 36 workers occupa-tionally exposed to mercury vapours (Langworth et al.22) Thewhite blood cell differential counts, serum autoantibodies and invitro production of the cytokines [IL-1, IL-6 and tumor necrosisfactor alpha (TNFa)] as well as CD3, CD4, CD8, CD14 andCD25 lymphocyte surface markers were determined. All of theimmunologic parameters were within normal ranges. However,in the group sensitized to mercury, there was a reduction of the

† Presented at The Sixth Nordic Symposium on Trace Elements in Human Health andDisease, Roskilde, Denmark, June 29–July 3, 1997.

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in vitro production of both TNFa and IL-1 compared with thereference values. The relatively small size of the study groupand low-level exposure to mercury vapours limited the generalsignificance of these results (Langworth et al.22)

The purpose of the present study was to find out whether ornot the biological effects of higher occupational exposure tometallic mercury are reflected in the quantitative changes of thepopulations of T-cells and NK-cells.

Experimental

The study was carried out in 37 males, aged 21 to 54 years old(X = 30.9 ± s = 8.0) with occupational exposure to mercuryvapours (Hg0) for up to 10 years (7 months to 9 years) (X = 4.2± 2.8) and 64 males aged 28 to 60 years (X = 47.0 ± 7.0) witha history of exposure from 10 to 37 years (X = 22.6 ± 7.3). Thesubjects worked in chlorine production by the electrolyticmethod in three 8 h shifts. Of these, 25 (68%) and 39 (61%),respectively, were smokers.

The control group comprised 36 males aged 28–55 years (X= 46.0 ± 8.7) not exposed to any chemical compounds orharmful physical influences; 29 (80.6%) were smokers. Theyworked also in a three-shift system in the same plant. Allworkers were subjected to medical examination for ruling outthose with diseases which might have affected their immunestatus. Alcoholics, and those regularly taking drugs andconvalescents after infectious diseases were disqualified.

The air for determination of metallic mercury concentrationswas taken with fixed samplers from area samples (Principles ofAir Sampling in Work Environment and Interpretation ofResults, Polish Committee of Norms, PN 89 Z 04008/07). Theair sampling was done at two different points in this workplace, according to the principles of stationary measurements(Gromiec and Rogaczewska.23) The air was sampled for 20 minusing a pump (the speed of sampling was 0.18 m3 h21),according to the Polish Committee of Norms, PN 69/C 13048.Air samples were taken in two different work places 6 times onmorning work shifts, during the work time of subjects exposedto mercury vapour. Aspirated air samples were flown to thereaction vessel, which contained 50 cm3 of 1% KMnO4 solutionin 10% H2SO4. The aspirated metallic mercury was oxidized toHg2+. After 20 min of air sampling, the excess of KMnO4 wasreduced using hydroxylamine hydrochloride. Thereafter, Hg2+

ions were reduced to metallic Hg0, by using tin(ii) chloride(SnCl2) and then Hg0 was removed by aeration and determinedusing an atomic absorption spectrometer (Coleman MercuryAnalyzer Mas-50, Perkin-Elmer, Norwalk, CT, USA,l = 253.7 nm). The detection limit of the analytical procedurefor determination of mercury in urine was 10 mg dm23 and inblood was 4 mg dm23. The ‘maximum permissible concentra-tion’ (MPC) of metallic mercury is 0.05 mg m23. The mercurycontent in urine and blood was determined by a method similarto that for Hg determination in air samples (AAS). The urineand blood samples were mineralized with KMnO4 in acidicmedium and the excess of the oxidizing agent was reduced withhydroxylamine hydrochloride. Thereafter the samples werereduced with SnCl2 in the aeration vessel and the liberatedmercury was removed by aeration. Urine was obtained between8:00 and 11:00 am for the determination of total mercury. Themercury concentration was expressed in mg dm23 of urineof specific mass 1.024 g. Collection of urine samples was madecarefully to avoid external contamination. The mercury concen-tration in urine has maximum values during evening andmorning hours and has minimum values in the afternoon(Piotrowski et al.,24 Wallis and Barber25) and therefore sam-pling time was during the morning hours. Blood samples formercury determination were obtained from the veins of fastingsubjects during the morning hours to avoid external contamina-

tion, together with blood samples for determination of T-cellpopulations.

For the determination of T-cell populations, BehringwerkeAG Diagnostica (Marburg, Germany) monoclonal antibodieswere used in indirect immunofluorescence tests. Heparinizedvenous blood was diluted 1 + 1 with normal saline, and overlaidon Ficoll/Paque (Pharmacia LKB Biotechnology, USA). Thistwo-phase system was centrifuged at 400 g for 30 min at18–20 °C. The lymphocytes from the interphase were washedtwice with normal saline to remove platelets, and suspended toobtain a concentration of 5 3 106 lymphocytes per cm3.(CD3+)T-cells were determined using monoclonal antibodiesBehring BMA 030. (CD4+)T-helper cells were found by meansof monoclonal antibodies Behring BMA 040, for (CD8+)T-suppressor cells monoclonal antibodies Behring BMA 081 andfor (CD16+)NK-cells monoclonal antibodies Behring BMA070 were used, always following the suggestions of theproducer (Behring). A 50 mm3 volume of cell suspension wasincubated for 30 min at +4 °C with 10 mm3 of propermonoclonal antibodies. Then, after washing the cells withphosphate buffered saline (PBS) and sodium azide (pH 7.6)(according to Pharmacia), anti-immunoglobulin rabbit serumlabelled with fluorescein isothiocyanate (Behring) was added.After 30 min of incubation at +4 °C the cells were washed withPBS and after supernatant removal they were suspended in 0.1cm3 of PBS.

The percentage proportions of T-cell subpopulations werecalculated with a fluorescence microscope (VEB Carl ZeissJena, Jena, Germany). The absolute number of CD3+, CD4+,CD8+ and CD16+ lymphocytes was calculated from the totalwhite blood cell count (determined by the chamber method),and from the differential white blood cell count. The results

Table 1 Effects of occupational exposure to metallic mercury on thepopulation of leucocytes, total lymphocytes and (CD3+)T-cells

Lymphocytes

Total (CD3+)T-cellsLeucocytes/

Group 3 109 dm23 an* % an* %

Control (C), n† = 36 —

X = 6.47 2.05 32.8 1.33 64.7± s = 1.59 0.56 7.0 0.43 8.5

Exposed to Hg0 for less than 10 years, n† = 37—

A‡§ AAA‡§ AAA§ AAA‡§

(I) X¶ XXX¶ XXX¶ XXX¶

X = 7.12 3.00 43.1 2.11 60.7± s = 1.63 0.75 10.1 0.66 10.2

Exposed to Hg0 for 10 to 37 years, n† = 64—

A‡§ AA‡§ AA§ AAA‡§

(II) XX¶ XX¶ XXX¶

X = 7.27 2.86 40.0 1.80 62.4± s = 1.92 0.78 7.7 0.61 9.2

All exposed to Hg0, n† = 101—

A‡§ AAA‡§ AA§ AAA‡§

(III) X¶ XXX¶ XX¶ XXX¶

X = 7.22 2.91 41.1 1.91 64.2± s = 1.81 0.77 8.8 0.64 9.8

* an, Absolute number (3 109 cells per dm3). † n, Number ofworkers. ‡ After logarithmic conversion. Statistical significance (C : I orC : II or C : III). § Analysis of variance (ANOVA): AAA = p < 0.001;AA = p < 0.01; A = p < 0.05. ¶ Cochran-Cox C test or Student’s t test):XXX = p < 0.001; XX = p < 0.01; X = p < 0.05.[NB No statistical significances were observed in the leucocytes and T-cellpopulations between workers (I) with < 10 and (II) those with > 10 yearsexposure to metallic mercury.]

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were subjected to normal distribution analysis by the Shapiro–Wilk Gaussian decomposition test. Thereafter, the resultsindicating normal distribution, without or after logarithmicconversion, were subjected to statistical analysis by a Cochran–Cox C test or Student’s t test. Analysis of variance (ANOVA)amongst all groups and comparison between the exposed groupswere also calculated.

In addition, the correlation coefficient was calculated for theanalysed immunological parameters and the influence of the ageof workers and the duration of exposure to metallic mercury onthese parameters was assessed.

Results and discussion

Air analyses conducted regularly since 1983 have demonstratedthat the maximum permissible concentration was exceeded bythe mean Hg0 values particularly in 1983 (1.8 times), in 1984(1.5 times), and in 1965, 1978 and 1980 (1.1 times). In relation,however, to the maximum Hg0 concentrations in these years theMPC was exceeded 6.5; 6.0; 3.8; 4.2; 2.8 times, respectively.The shift time weighted average (TWA) of mercury determinedbefore research was 0.028 mg m23.

All mercury exposed and non-exposed workers of the controlgroup were regarded as healthy. The socioeconomic status of allworkers in this study was similar. The urine mercury level of theexposed workers ranged from 20 to 240 mg dm23 (X = 81.4 ±60.9) and in the blood from 4 to 72 mg dm23 (X = 18.3 ± 15.0).The levels of mercury in urine and in blood in the control groupof non-exposed workers were also determined. Both levels werelow, below or a little above the sensitivity border of the mercurymethod determination. In 20 workers of the control groupmercury levels in urine were below 10 mg dm23 and in bloodbelow 4 mg dm23. In 16 workers of the control group mercurylevels were a little above the border of sensitivity and were

X = 10.39 ± 5.01 mg dm23 in urine and X = 4.12 ± 2.57mg dm23 in blood.

Stimulation of the T-cell line in workers exposed to metallicmercury was evidenced by a 58.6% (p < 0.001) increasednumber of (CD3+)T-cells in the workers exposed to mercuryvapours for < 10 years or by 35.3% (p < 0.001) in the workersexposed for > 10 years and by a 59.5% (p < 0.001) increasednumber of (CD4+)T-helper cells in the workers exposed for< 10 years or by 48% (p < 0.001) in the workers exposed for> 10 years and by an increased number of (CD8+)T-suppressorcells of 96% (p < 0.001) in the workers exposed for < 10 yearsor by 81% (p < 0.001) in the workers exposed for > 10 years.The lower increase in count of (CD3+)T-cells than (CD8+)T-suppressor cell population caused the decreased value of the(CD3+)T/(CD8+)T-suppressor ratio by about 18% (p < 0.05)in the workers exposed for < 10 years or by 25% (p < 0.01) inthe workers exposed for > 10 years. The lower increase in countof (CD4+)T-helper cell than (CD8+)T-suppressor cell popula-tion was the cause of the decreased value in the (CD4+)T/(CD8+)T-suppressor ratio by about 18% (p < 0.05) in theworkers exposed for < 10 years or by 16% (p < 0.05) in theworkers exposed for > 10 years. No changes were observed inthe T-cell populations between workers exposed for < 10 yearsand those exposed > 10 years (Tables 1 and 2). No statisticallysignificant changes were observed in the T-cell populationsbetween workers with up to 10 years exposure and those with> 10 years exposure. Occupational exposure to mercury causeda fall in percentage (CD16+)NK-cells but the absolute count ofthese cells in the exposed subjects was not different from that innon-exposed subjects.

No statistically significant correlation was observed in agroup of all workers exposed to Hg0 between their age and anyother analysed parameters (correlation coefficient, r, wasbetween 20.11 and 0.10). In addition, statistical analysis of theeffects of age and duration of exposure to metallic mercury on

Table 2 Effects of occupational exposure to metallic mercury on the population of T-cells, NK-cells, (CD3+)T/(CD8+)T-suppressor and (CD4+)T-helper/(CD8+)T-suppressor ratio

Lymphocytes

(CD4+)T- (CD8+)T- (CD16+)NK-helper cells suppressor cells (CD3+)/ (CD4+)/

/(CD8+) /(CD8+)Group an* % an* % an* % cells cells

Control (C), n† = 36—X = 0.84 41.30 0.47 22.70 0.26 12.70 2.96 1.90± s = 0.30 7.84 0.18 4.91 0.14 3.10 0.73 0.60

Exposed to Hg0 for less than 10 years, n† = 37—AAA‡§ AAA‡§ AAA§ AAA§ A‡§ AA‡§

(I) XXX¶ XX¶ XXX¶ XXX¶ X¶ X¶

X = 1.34 42.90 0.92 30.82 0.22 7.30 2.43 1.56± s = 0.48 8.87 0.29 9.82 0.13 3.90 0.94 0.66

Exposed to Hg0 for 10 to 37 years, n† = 64—AA‡§ AAA‡§ AAA§ AAA§ AA‡§ AA‡§

(II) XX¶ XXX¶ XX¶ XXX¶ XX¶ X¶

X = 1.24 43.52 0.85 29.56 0.19 6.60 2.23 1.60± s = 0.45 9.58 0.35 7.87 0.11 3.50 0.56 0.62

All exposed to Hg0, n† = 101—AAA‡§ AAA‡§ AAA§ AA‡§ AA‡§

(III) XXX¶ XXX¶ XX¶ XXX¶ X¶ X¶

X = 1.27 43.31 0.88 29.27 0.20 6.86 2.30 1.59± s = 0.46 9.30 0.33 8.56 0.12 3.64 0.71 0.63

* an, Absolute number (3 109 cells per dm3). † n, Number of workers. ‡ After logarithmic conversion. Statistical significance (C : I or C : II orC : III). § Analysis of variance (ANOVA): AAA = p < 0.001; AA = p < 0.01; A = p < 0.05. ¶ Cochran-Cox C test or Student’s t test: XXX = p <0.001; XX = p < 0.01; X = p < 0.05.[NB No statistical significances were observed in the leucocytes and T-cell populations between workers (I) with < 10 and (II) those with > 10 years exposureto metallic mercury.]

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z = 46.23–0.155x + 0.078y

36.80437.82838.85239.87640.89941.92342.94743.97144.99546.018

57.67459.03760.40061.76263.12564.48865.85167.21468.57669.939

z =63.195 + 0.108x + 0.213y

z = 41.269 + 0.015x + 0.087y

41.47641.89742.31742.73843.15843.57944.00044.42044.84145.261

z = 29.839 + 0.015x + 0.028y

29.13029.30929.48829.66729.84730.02630.20530.38430.56430.743

z = 1.909 + 0.017x – 0.02y

1.5381.6961.8542.0112.1692.3272.4852.6422.8002.958

the studied immunological parameters indicates that exposureduration may affect some of the values (Figs. 1–6). Theresponse surfaces show that, in particular, the percentage of thetotal lymphocytes (Fig. 1) and the (CD4+)T-helper cells (Fig. 3)was greatly affected by exposure to metallic mercury. Theresponse surfaces in Figs. 5 and 6 show duration of exposuredependent decreases in (CD3+)T/(CD8+)T-suppressor ratioand (CD4+)T-helper/(CD8+)T-suppressor ratio.

The mechanism of mercury action on the human lymphocyteshas only been studied a few times previously. It has not beenestablished whether or not during occupational exposuremercury accumulated in lymphocytes. X-ray analysis by energydispersion and wave dispersion spectrometers demonstratedthat in certain diseases, e.g., laryngeal carcinoma, the amount ofHg and also Pb, Cl, Bi, Mo, Cd, Ru, Te, Sr, W and Re increasesin circulating lymphocytes (Pilch et al.,26). The effect ofmercury on the lymphocytes seems to be connected withchanges in the level of free calcium in the cytoplasm. Theincubation of rat T-cells with methylmercury or with HgCl2 inthe presence of calcium ions demonstrated increased calciumcontent in the cytoplasm (Tan et al.27) Methylmercury increasedCa content rapidly through enhancing its influx through calciumchannels and mobilization of Ca2+ from the intracellular

Fig. 1 Response surface showing the effects of duration of exposure toHg0 and age of workers on percentage of the peripheral blood lympho-cytes.

Fig. 2 Response surface showing the effects of duration of exposure toHg0 and age of workers on percentage of the peripheral blood (CD3+)T-cells.

Fig. 3 Response surface showing the effects of duration of exposure toHg0 and age of workers on percentage of the peripheral blood (CD4+)T-helper cells.

Fig. 4 Response surface showing the effects of duration of exposure toHg0 and age of workers on percentage of the peripheral blood (CD8+)T-suppressor cells.

Fig. 5 Response surface showing the effects of duration of exposure toHg0 and age of workers on percentage of the peripheral blood (CD3+)T/(CD8+)T-suppressor ratio.

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z = 1.302 + 0.008x – 0.002y

1.3731.4171.4611.5051.5481.5921.6361.6801.7241.767

organelles. In the case of HgCl2 the increase in Ca2+ was muchslower because it came only from the incubation medium.

The present study demonstrates that occupational exposure tomercury stimulated the T-cell line but was without anyimportant effect on the count of NK-cells. Only the proportionof NK-cells decreased. Quantitative changes of T-helper cellsare thus the immunological indicator of the biological effects ofexposure to mercury.

HgCl2 induces a (CD4+)T-cell-dependent systemic autoim-mune disease in susceptible strains of rats and mice. In rats,autoreactive T-cells were shown to be involved, whereas inmice, attention has focused on the demonstration of ‘Hg-specific’ T-cells (Kubicka-Muranyi et al.28) Also in miceinduction of systemic autoimmunity by mercury was strictlydependent on T-cells, specifically (CD4+)T-helper cells (Hult-man et al.29) Stimulation of the immune system by metallic Hgwas confirmed also by other authors (Bencko et al.,20 Izdebska-Szymona and Kopec-Szlezak,15 Queiroz et al.,29 White andBrandt.30) The increased counts of lymphocytes, T-cells, T-helper and T-suppressor cells, with normal NK-cell count inperipheral blood were found in dental students but not inmedical students (Eedy et al.31) The former had contact withmercury vapours during practical classes, and mercury-contain-ing amalgam is a widely used material in dentistry. Amalgamfillings continue to release microamounts of mercury which canbe traced in saliva, blood, urine and even in the exhaled air ofindividuals having such fillings. Discussion has been continu-ing for many years to assess whether or not this is a health risk.In two subjects an increase in percentage of T-cells in peripheralblood was noted after removal of amalgam fillings (Eg-gleston.32) Recently a number of immunological tests werecarried out after the insertion of the first amalgam fillings andafter removal of such fillings, however, no changes were foundin the count of T-cells, helper and suppressor cells and NK-cellsin the peripheral blood of these subjects (Wilhelm et al.33)

Conclusion

The quantitative changes in T-cell populations as well aschanges in (CD3+)T/(CD8+)T-suppressor ratio and (CD4+)/(CD8+)T-suppressor ratio in peripheral blood of workersexposed to metallic mercury may represent an immunological

indicator of the degree of exposure and may be useful inmonitoring the immunotoxicity of mercury.

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Paper 7/05558GReceived July 31, 1997

Accepted October 30, 1997

Fig. 6 Response surface showing the effects of duration of exposure toHg0 and age of workers on percentage of the peripheral blood (CD4+)T-helper/(CD8+)T-suppressor ratio.

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nloa

ded

on 2

6/10

/201

4 00

:24:

32.

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