Belonging to the group of heavy metals, lead is a known and used element since the beginning of the human civilization. Nowadays it keeps being used in a wide range of industries such as the arms and the explosive, the accumulators, the chemical industry or ceramics. Most cases of lead poisoning are due to occupational exposure to this toxic element. For years, Sibiu County is in the top cities in terms of professional morbidity by chronic lead poisoning in Romania, due to the operation of the enterprise of non ferrous metallurgy Sometra S.A. from the town of Copsa Mica. All the measures of modernization from the latest years have not been enough because important noxious quantities of inorganic lead continue to be overrun, thing which is reflected in a significant number of occupational lead poisoning and in the percentage of the after effects of this illness. The effects of the lead towards the digestive system were systematized in the digestive syndrome, with symptoms of chronic or acute chronic manifestations as the lead colic. In addition to these typical manifestations in chronic occupational poisoning a number of diseases are associated, as gastrointestinal ones like the peptic ulcer and the liverish ones like the fatty liver or chronic toxic hepatitis. Data from the speciality literature regarding the effects of lead to the digestive system are few and refer specifically to the observations resulted from the experiments to animals; that is why I considered to be of interest the study of these effects to the workers exposed to this toxic element. Digestive diseases, both the gastrointestinal and the liverish ones, are diseases determined both by the factors related to the way of live (food, the habit of smoking, to consume alcohol, etc) and by the genetic or infectious factors which produce the disease. It is also important to know for the workers exposed to lead, the magnitude of the professional factor which determines the digestive disease, so I proposed that the results of the studies from this paper form the basis of a health programme that will include recommendations for monitoring and control of these diseases for the categories of workers with the highest risk of exposure. The paper covers two separate studies, which have different objectives. The first study aimed to explore the relationship between the occupational exposure to inorganic lead and the gastrointestinal diseases; the chronic gastro duodenitis and the chronic peptic ulcers. The second study aimed to explore the effects of the 1
lead to liver and the influence exercised to the liverish enzyme systems by this toxic element. The thesis includes a total of 293 pages, its content being structured in 15 chapters. The first 4 chapters are the general part and contain data from the speciality literature related to the approached themes. The next 10 chapters from the part with the personal investigations include the study about the gastrointestinal effects, the study about the liverish toxic effects of the lead. The last chapter is a health programme for the prophylaxis of the digestive diseases related to the workers exposed to the lead, where I used the data obtained previously. Study I. Investigations Regarding the Gastro Duodenitis Affections at the Patients with Occupational Exposure to Inorganic Lead In chapter 5, I presented the working hypothesis, which approaches the premise that because of the properties of the lead, of the toxic kinetics and of the mechanisms of the action physiopathology, the lead may become an etiological factor for the development of the ulcerative disease acting for the augmentation of the chlorine peptic aggression towards the mucosa and influencing the mechanisms, which constitute the three barriers to defend the digestive mucous membranes. The aim of this study is to obtain results which will form the basis of a health programme to reduce the risk of the appearance of the digestive diseases associated with chronic lead poisoning, where the periodic control of the workers' health condition exposed to, includes recommendations for the evaluation of the stomach diseases and of the duodenum depending on the found risks. The objectives of the study were: To make know the prevalence of the affections of the stomach and of the duodenum at the people with occupational exposure to inorganic in comparison with other similar experiments; To assess the relationship between the occupational exposure to inorganic lead and the emergence of the diseases of the stomach and of the duodenum. The study (chapter 6) was represented by a group of selected employees of the company "SOMETRA" Copsa Mica, who were hospitalized in the Professional Diseases Clinic of the Hospital Council Emergency Sibiu during the period January 2005 September 2008 with the diagnosis of chronic inorganic lead poisoning. 2
As experiment for the comparison, I chose a group of employees of the company Independenta S.A. Sibiu, who work in the branch of industry of machinery with no exposure to lead at work. The methodology of work, described in subchapter 6.2, included more conclusions, achieved through the improved methods: The determination of the inorganic lead in the atmosphere of the jobs The determination of the quantity of the lead in blood The determination of the quantity of the lead in urine The determination of the delta amino levulinic urinary acid The determination of haematological indicators: haemoglobin and HCT. After these determinations, the methodology of work consisted of the following main coordinates: The description of the economic units from the study The study of the existent correlations between the indicators of exposure and the ones of biological effect at the study group The analysis of the morbidity by gastric and duodenal ulcer at the enterprise Sometra S.A. compared with the morbidity from Romania and the county of Sibiu The analysis of the morbidity by gastro duodenal diseases at the study group compared with the other group The analysis of the relationship between the gastric and duodenal ulcer and the occupational exposure to lead The analysis of the risk factors for the gastric and duodenal ulcer at the compared group The analysis of the relationship between the chronic gastroduodenitis and the occupational exposure to lead The analysis of the risk factors for the chronic gastro duodenitis at the compared group The methodology of the statistical data processing: Excel programme was used for the realization of the database. These data were subsequently exported to the Medcalc programme, which was used for the primary and advanced statistical processing. 3
Study II Investigations Regarding the Liverish Toxic Effects of the Exposure to Inorganic Lead In this study I started working on the hypothesis (chapter 10) that lead may cause the disruption of the physiology of the metabolism, the increasing of the oxidative stress and the induction of the pro infecting mediators at the liver, leading to the deterioration of the function of the liver and of some diseases like the chronic professional saturnine, fatty liver. The aim of the study was that the results be used for a health programme to reduce the impact of toxic effects of lead to the liver and liver functions. The objectives of the study were: The determination of the prevalence of the liver disease at the patients with occupational exposure to inorganic lead comparative with the other unexposed group The evaluation of the relationship between the occupational exposure to inorganic lead and the appearance of the hepatitis The investigation of the liver functions at the patients with occupational exposure to lead comparative with the other unexposed group The assessment of the relationship between the occupational exposure to lead and the change of the liver functions. In chapter 11, I wrote about the study and compared group. So, the study group was first used in research, consisted of 124 subjects and another small group of 37 subjects from the most polluted sections, who were also examined to find out the quantity of the lead from the blood. At all 124 subjects a photo of the liver was done. Also, the body mass index (BMI) was calculated and the patients with BMI>30kg/m 2 were considered obese. Laboratory tests have also pursued beside the parameters of exposure and biological effects related to exposure to inorganic lead, the following biochemical indicators: glycerine, trans amylases (ASAT, ALAT), bilirubin, glutei, alkaline phosphates, cholinesterase serum, total protein, cholesterol and triglycerides. The compared group was composed of patients hospitalized during a year in medical section of the County Clinic Hospital Emergency Sibiu. It was compared to the study group in terms of age and gender and without personal history of pathological aetiology of chronic viral hepatitis, without consumption of drugs, which are potential inductors of the fatty liver, 4
without surgery that could be associated with fatty liver. The alcohol consumers were excluded. The methodology of work, detailed in subchapter 11.2, covered, in addition to the first study, the following determinations: The determination of the blood glucose The determination of the trans amylases (ALAT) The determination of the aspartame trans amylases i (ASAT) The determination of the glutei (GGT) The determination of the serum alkaline phosphates (FAS) The determination of the total bilirubin (BT) The determination of the direct bilirubin (BD) The determination of the total protein (PT) The determination of the serum cholinesterase (Che) The determination of the blood cholesterol (C) The determination of the blood triglycerides (Tg) The description of ultrasound method for diagnosing fatty liver After making these determinations, the Protocol has followed the next main steps: Analysis of indicators of exposure and biological effect at the study group Analysis of morbidity by liver disease at the study group compared with the other group Analysis of the relationship between occupational exposure and the fatty liver Analysis of risk factors for fatty liver at the compared group Analysis of the relationship between chronic toxic hepatitis and occupational exposure to lead Analysis of biochemical indicators of liver metabolic activity in the study group compared with the other group. Associations with statistical significance (presented in Chapter 13 "talk") that I have identified at the group with exposure to lead in the two studies, are centralized in the chart no. 1. 5
Chart no. 1 The Associations with Statistical Significance between the Variables Investigated In Studies to Gastro Duodenitis Diseases and Liverish Toxic Effects in Patients with Occupational Exposure to Inorganic Lead Nr. Investigated Variables P crt. 1. Lead in blood and urine 0,0251 2. Lead in blood and urine (fitting with the seniority) 0,0470 3. Lead in urine delta amino laevulin urinary acid <0,0001 4. Lead in urine delta amino laevulin urinary acid (fitting <0,0001 with the seniority) 5. Lead in urine seniority 0,007 6. Gastro duodenitis diseases phase III of saturnine 0,0907* 7. Liverish diseases phase III of saturnine P=0,0910* 7. Peptic ulcer lead in blood 0,0826* 8. Peptic ulcer lead in blood over 65µg/dl 0,037 9. Peptic ulcer lead in blood over 65µg/dl(adjusting for 0,061* smoking, age and seniority) 10. Ulcer lead in urine 0,0173 11. Ulcer lead in urine (adjusting for smoking, age and 0,0784* seniority) 12. Peptic ulcer lead in urine over 250µg/l 0,037 13. Peptic ulcer lead in urine over 250µg/l (adjusting for 0,0508* smoking, alcohol consume, age and seniority) 14. Peptic ulcer over 15 years of work (adjusting for 0,0502* smoking, alcohol consume, age and lead in blood) 15. Chronic gastro duodenitis lead in blood over 65µg/dl 0,0907* (adjusting the variables which can influence the presence of the fatty liver) 17. Fatty liver lead in blood 0,0110 18. Fatty liver lead in blood (adjusting the variables which 0,0275 can influence the presence of the fatty liver) 19. Fatty liver lead in blood over 50 µg/dl, at the persons 0,0640* with more than 15 years of work (adjusting the variables which can influence the presence of the fatty liver) 20. Fatty liver lead in urine 0,0007 21. Fatty liver lead in urine (adjusting the variables which 0,0214 can influence the presence of the fatty liver) 22. Fatty liver lead in urine over 200µg/l, at the persons with 0,0496 more than 10 years of work (adjusting the variables which can influence the presence of the fatty liver) 23. Fatty liver lead in urine over 200µg/l, at the persons with 0,0231 more than 15 years of work (adjusting the variables which can influence the presence of the fatty liver) 24. Fatty liver D ALA 0,0383 25. Fatty liver D ALA (adjusting the variables which can influence the presence of the fatty liver) 0,0467 6
26. Fatty liver D ALA over 15 mg/l, at the persons with more than 10 years of work (adjusting the variables which can influence the presence of the fatty liver) 27. Fatty liver D ALA over 15 mg/l, at the persons with more than 15 years of work (adjusting the variables which can influence the presence of the fatty liver) 28. Negative correlation FAS D ALA (fitting with seniority and age) 29. Total bilirubin lead in urine (fitting with the seniority and age) 30. Cholesterol over 200 mg/dl the seniority of the occupational exposure to lead 31. Triglycerides the seniority of the occupational exposure to lead * Tendency of statistical significance 0,0112 0,0080 0,0836* 0,0237 0,0790* 0,0351 In chart no. 2, I have centralized the most significant differences between the employees exposed and not exposed to lead regarding some biochemical indicators of liver function. Chart no. 2 The Registration of the Significant Statistical Differences between the Exposure Group and the Other One from the Study Regarding the Liverish Toxic Effects of Lead Nr. crt. Investigated Variables Significant Differences, P 1. ASAT at study group bigger than ASAT at compared 0,0011 group 2. GGT at study group less than GGT at compared group < 0,0001 3. FAS at study group less than FAS at compared group < 0,0001 4. No. of cases with FAS under the inferior limit of the 0,007126 normal more than no. of witnesses FAS under the inferior limit of the normal 5. No. of cases with hyper structural bilirubin diseases 0,002402 more than no. of witnesses with structural hyper bilirubin diseases 6. Tg at study group bigger than Tg at compared group 0,0357 Chapter 14 Final Conclusions 1. More than 70% from the patients of the study group from Sometra Copşa Mică had the values of the lead in urine very big (over 250µg/l). More than 70% from the investigated subjects had the level of the lead in blood over 50 µg/dl; more than 57% of the patients from the study group had the values of 7
the delta amino levulinic urinary acid over 20 mg/l; more than 55% from the patients of the study group had the anaemic syndrome. 2. There is a statistically significant valid correlation between the level of the lead in blood and urine, whether the adjustment is made for seniority; delta amino levulinic urinary acid level correlates statistically significant with the level of the lead in urine. 3. There is a significant risk of a stomach and duodenum illness at the group with exposure to inorganic lead, compared to unexposed one. Also, there is a significant risk of fatty liver at people exposed to lead, compared with the unexposed ones. 4. The prevalence of peptic ulcers in SOMETRA Copşa Mica enterprise is greater than the prevalence of peptic ulcers in the county of Sibiu and Romania, the tendency for the investigated period is to increase the prevalence. 5. Ulcer occurs in lower seniority at the group exposed to lead; the difference towards the unexposed group to lead approaches the threshold for statistical significance. 6. The average level of the lead in blood is higher in cases with ulcer, the difference compared to those without having ulcer having statistical significance. The values of the lead in urine are significantly higher in patients with ulcers compared with those without ulcers from the study group. 7. There is a positive correlation with a tendency of statistical significance between the presence of peptic ulcers and lead in blood (P = 0.0826). This is statistically significant (P = 0037) at the lead in blood over 65μg/dl. There is a statistically significant positive correlation between peptic ulcer and lead in blood (P = 0.0173). This association exists and is statistically significant in patients whose lead in urine exceeds 250μg / L (P = 0037). 8. At the persons who have no occupational exposure to lead, there are statistically significant correlation between age and ulcer and between ulcer and seniority. 9. Fatty liver appears at average ages, which are significantly lower at persons exposed to lead comparative with those who are not exposed. Among the 8
conditions associated with fatty liver, obesity is rare in people exposed to lead; the difference from unexposed ones is statistically significant. Also, diabetes was not associated in any cases with fatty liver and with exposure to lead; instead it affected about a quarter of cases with fatty liver which were not exposed to lead. 10.Patients with fatty liver had the average values of the indicators of the lead in blood and in urine but the values of the delta amino laevulin urinary acid is higher at patients without fatty liver, the difference being statistically significant. 11.There are statistically significant positive correlations between the presence of the fatty liver and the lead in blood and the lead in urine and delta urinary amino laevulin acid. 12. At the persons who do not have occupational exposure to lead, there are significant correlation statistically between fatty liver and obesity, among diabetes, cholesterol, triglycerides and age. 13.The study group ASAT is significantly bigger than the unexposed group to lead (P=0, 0011); but the values ASAT do not correlate positively only with a single indicator of the exposure to the lead, namely the lead in blood and the correlation is not significant statistically. 14. Both studied enzymes "of cholestasis", GGT and FAS had significant less values at the group exposed to lead than the unexposed group. More than that, the number of persons with FAS under the inferior limit of the normal at the study group is significantly bigger than at the ones with lower FAS from the compared group. There is a negative correlation with a tendency of statistical signification between the delta amino laevulin urinary acid and FAS, adjusting for the age and seniority. 15. There is a positive and significant correlation statistically between the total bilirubin and the lead in urine bilirubin, which maintains even after the adjusting for the age and seniority. The structural hyper bilirubin predominates at the patients with exposure to lead (associated to the fatty liver or toxic hepatitis) while at the compared group the hyper bilirubin is less because the functional ones, which appear on the unaffected liver predominate. 9
16.The hyper cholesterol at the study group correlates positively with the period of exposure to lead, this correlation having the tendency of statistical significance. The triglycerides at the group exposed to the lead are bigger than at the unexposed group. Their level correlates positively at a significant statistical level with the period of exposure to lead. The cholesterol and the triglycerides at the unexposed persons to lead correlates with their age. 17. I consider that the digestive studied diseases (peptic ulcer, chronic gastroduodenitis, fatty liver) having the professional etiologic fraction more than 20%, are diseases related to work. 10