Biological age is an integral parameter of the health status of agricultural workers who have suffered acute and chronic pesticide intoxication

  • Authors: N.M. Bubalo, G.M. Balan
  • UDC: 572.79:615.9
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L.I. Medved's Research Center of Preventive Toxigology, Food and Chemical Safety Ministry of Health of Ukraine, Kyiv, Ukraine

Abstract. Objective. To analyze and summarize the literature data on the main biomarkers of biological age (BA) and assess the contribution of acute and chronic intoxication of pesticides to the rates of aging and the formation of BA in agricultural workers.
Materials and Мethods. About of 186 agricultural workers were examined with acute pesticide poisoning (46 with poisonings with organophosphorus pesticides, 8 with synthetic prntroidamides, 132 with acute poisoning with herbicides based on 2,4-dichlorophenoxy-cetic acid, and 62 with chronic intoxication with pesticides and 60 practically healthy individuals. The biological age (BA) was evaluated according to the method of V. Voitenko (4th variant).
Results of the Research. An increased rate of aging and an increase in the ratio of integral BA to due BA in patients who had acute and chronic intoxication with pesticides, especially with toxic hepatitis syndrome are revealed.

During the life activity in the human body, there are aging processes that are characterized by a progressive decrease in physical, mental and reproductive functions, leading to a decrease and even loss of functions of various organs, increased sensitivity to infectious diseases, an increase in chronic general somatic diseases, and ultimately, to death. In some studies, it has been shown that in the same age groups the intensity of ageing processes of different individuals varies significantly [1,2,3].

Purpose of the study. Analyse and summarize the literature data on the main biomarkers of biological age (BA) and assess the contribution of acute and chronic pesticide intoxication in agricultural workers to the rate of ageing and BA formation. Compared to the general population ageing processes is more intense in persons with chronic general somatic, infectious and oncological diseases, as well as in persons abusing alcohol, smoking, drugs, persons being often under the influence of stress and xenobiotics [1-4].

Chronological or calendar age (CA) is the most acceptable parameter of ageing. But the rate of ageing of the body different systems in study individuals is significantly different. That is why it was suggested to evaluate the biological age (BA) using various battery tests and mathematical models that characterize ageing of the body main systems (cardiovascular, broncho-pulmonary, nervous, as well as general physical condition, functional state of the visual and auditory analysers, and etc.) [1-7]. It is proposed to evaluate both partial BA — a functional state of the body separate system as well as an integral biological age (IBA) along with an integral evaluation of the ageing rate of various systems of the body [1, 2]. Depending on the methods of its determination, BA may reflect a reduction in the functional capabilities of the body, its ability to function and viability compared to the proper biological age (PBA), averaged for a group of people with a similar calendar age [1-6]. The authors believe that BA is evaluated based not on years lived from birth, but on the distance from the moment of death.

An important issue is the selection of tests that most adequately determine the person’s BA. There is currently no generalized set of anthropometric, clinical-physiological, psychological and laboratory parameters that would satisfy most of the researchers involved in the determination of BA [1-6]. Moreover, according to some authors, the same tests are characterized by a high coefficient of correlation with CA, according to others — by low one. Recently, however, attempts have been made to use the evaluation of the ageing rate and BA as an integral parameter of the impact of working conditions, lifestyle, bad habits and various past diseases on the health of the subjects [3-7].

Aging is a global health problem. In general, the number of people over the age of 65 is estimated to increase from 420 million in 2000 to 973 million in 2030 [8]. Aging, as a rule, is accompanied with chronic diseases, disability, a decrease in the quality of life, emergence of social problems and an additional burden on the health system and society. All this requires the intensification of research on the identification of biological components that affect the ageing of people, increase in BA, development of diseases that occur with age. Identification of biomarkers of ageing rate and especially low BA is necessary for the development of preventive measures aimed at preventing premature ageing [1, 3-6, 8].

In recent years impaired epigenetic regulation of genome architecture and appearance of DNA hypermethylation is of a great importance in premature ageing. This is accompanied by slowed gene expression, with minimal involvement in the cell cycle, apoptosis, detoxification and cholesterol metabolism [9-16]. It is noted that epigenetic changes as a function of ageing occur in many tissues and may serve as biomarkers for both calendar and BA. The severity of the epigenomic modification as DNA hypermethylation is significantly different in different tissues, depending on the ageing rate [15, 16, 23]. DNA methylation is particularly noticeable with age which is observed in the genomes and genes involved in cell differentiation [17, 23]. It has been shown that microRNA (mRNA) influence the expression of genes in the ageing process [8, 17-19], affecting life expectancy due to disturbances in many loci. Some mRNAs reflect the fast ageing rate, correlate with high biological age, and others, on the contrary, characterize longevity [18-20]. It should be noted that the ageing process accelerates the oxidative stress caused by chemical, physical and other environmental factors, therefore the parameters of lipid and protein oxidation are proposed to use as biomarkers of acceleration of the ageing rate and BA [21, 29]. It has also been shown that folic acid, vitamins B12, retinoic acid, resveratrol, curcumin, sulforaphane, sirtuin 1 and tea polyphenols can simulate epigenetic patterns, reduce the rate of DNA methylation by affecting enzymes that channel DNA methylation processes and modify histones [21,22] and thereby slow down the aging rate and reduce BA [24-27]. In recent years, it has been shown that with the ageing of the body and increase in BA, there is a shortening of the telomere cell length and period of cell differentiation [30]. Because of this, the telomere length is justified as one of the most informative BA biomarkers, although its evaluation is economically sufficiently costly.

Different parameters and biomarkers are suggested for qualitative and quantitative assessment of biological age. The process of ageing is accompanied with the deficit of various functions (physical, cognitive, sexual, etc.). The accumulation of the function deficit with age, which is measured by different health parameters, varies from 20 to 92 % (a deficit grows by approximately 2–3 % per year) [28]. At the same time, there is a non-linear increase in the growth rate of the function deficit in each individual, depending on the past diseases, stress, environmental factors, labour activity, and others. Comprehensive evaluation of the deficit of functions of various organs is a reliable BA parameter [28]. The deficit of the functions of various systems of the body in the process of ageing leads to general weakness, frailty or fragility. L. P. Fried et al. [32] describe the state of frailty in the presence of three of the following five function deficits: weight reduction, cachexia, decreased muscular strength, slowed down walking and decreased physical activity. The severity of the function deficit is not so much related to the calendar age, but with BA. Different sets of frailty parameters and rates or index of function deficit (FI) are proposed for frailty quantitative evaluation [32,33]. At the same time, the authors attempt to quantify the physiological deregulation that underlies the general weakness. The authors believe that the function deficit indices are reliable BA parameters and can be used to predict the terms of the next life of the individual. The risk of death increases exponentially with the function deficit accumulation. It is proposed to use the Function Deficit or Frailty Index (FI) to assess the role of various genetic or environmental factors in reducing health quality.

In the authors’ opinion, energy metabolism parameters in experimental animals are the main components of the function deficit index. The total daily energy expenditure (TDEE) is proposed to be divided into three main components: metabolism rate or resting metabolic rate (RMR), activity energy expenditure (AEE), and diet-induced thermogenesis.

For a clinical evaluation of the deficit or BA indices in the study subjects, Kim S. et al. [28] suggest the use of the following biomarkers: age, sex, body weight, thyroid hormones T3 and T4, insulin-like growth factor 1 (IGF1) and creatine phosphokinase (CPK). The authors believe that the use of these biomarkers adequately reflects the contribution of genetic and environmental factors to BA formation. In turn, Bae C.-Y et al. [34] propose clinical parameters related to the constitution and based on the structure of body fat as a BA biomarker. The authors note that BA is evaluated by the individual’s functional status compared to his/her chronological peers on the basis of how s/he works in comparison with other people of the same chronological age. BA evaluation was performed with a correlation of CA in 243 778 Korean residents aged 20 to 90 years. The following clinical parameters were studied: height, weight, body mass index (BMI), hip circumference, body fat mass percentage (BFM%), lean body mass percentage (LBM%). In this case, BMI (kg/m2) was evaluated as a partial division of body weight (kg) by height2 (m2). BFM% and LBM% were determined using multifrequency segmental bioelectric impedance. The informative model of BA evaluation according to the structure and weight of the body was substantiated on the basis of the correlation analysis with chronological age and health status, which the authors suggest using when examining large contingents in the surveillance dynamics.

In another study by Bae C.-Y. et al [35] attempted to assess BA using clinical biomarkers that reflect the function of the five major organs of the human body (heart, lungs, liver, pancreas and kidneys) in 121,189 Korean people aged 20 and over. The evaluation included six anthropometric parameters that were studied in the previous study [34] and an additional 28 biochemical tests, reflecting the function of the above bodies. The correlation between the study parameters demonstrated the correlation between the chronological age, structural anthropometric, clinical and biochemical biomarkers.

The informational value of the biomarkers used to evaluate the ageing rate and health status of the population was studied. It included biomarkers that reflect the state of the cardiovascular system, metabolic processes, inflammation, function of the hypothalamic-pituitary axis (HPA), sympathetic nervous system (SNS), as well as the function of the kidneys, lungs, heart, nervous system and genetic markers [37]. It was noted that the studied biomarkers were sufficiently informative for estimating the ageing rate and predicting increased mortality risk, as well as the existence of associative links between biomarkers characterizing the functional states of different systems of the body.

Jackson S.H.D. et al [38] discuss the possibility of BA measuring after the study of the informative value of 16 biomarkers, including the concentration of prostacyclins in rat fibroblasts, viscosity of cell membranes, electroretinography, baroreflex regulation of the cardiac rhythm, haemogram, corneal and buccal epithelium cells, muscular strength and vital capacity of the lungs. The authors came to the conclusion that these biomarkers are sufficiently informative to assess BA and ageing. At the same time, there is an association between fluctuations of physiological tests and age. It has been studied that tests contribute to the objectification and quantitative evaluation of BA.

Summarizing the informative value of the existing general BA evaluation methods Jia L. et al. [36] note that there is currently no “golden index” for the evaluation of aging and BA, despite a significant number of existing test models based on the studied physical, physiological and biochemical parameters of the body and their factor analysis. Although it is found that different organs age at different speeds because genetic factors play an important role in the process of ageing. The authors note that different ways to assess BA have their advantages and disadvantages. Each researcher should choose the most appropriate method depending on the number of subjects, the task of the experiment, conditions of the examination, funds, etc. The informative value of many battery tests for assessing BA is practically the same [36].

Most researchers argue that the use of BA assessment as an integral parameter of the human body is that it characterizes the physiological status of a particular individual at the time of the examination, while CA reflects a wide range of fluctuations of morphological and functional characteristics at the population level. It is shown that under the influence of harmful working conditions, the ageing rate increases almost twice in the setting of the low average annual intensity of production factors, 3–4 times — for moderate, 5–10 times — for high [6]. The study of the BA index among workers of various trades in the metallurgical industry and meat industry, depending on the working shift and day of the working week, showed that the BA in the workers working in the evening shift increases by 3 years, and on the 5th day of the working cycle — by 3.5 years [4]. After weekends there is a recovery of parameters, less noticeable in the group of workers with intense work. The authors note that BA assessment allows us to assess the impact of working conditions on the functional state and health of the workers and suggest using this test as an integral parameter that most adequately reflects the intensity of the impact of a complex of different harmful production factors, which can be a significant addition to the definition of the class of working conditions of the worker. The increase in BA is not only due to the interaction of unfavourable production factors, but also due to a general somatic pathology. Yes, in women, both with diabetes mellitus and with chronic alcoholism, there is a sharp increase in cardiopulmonary BA from 3 to 10 years in different age groups [1].

It is suggested to rank health assessments, referring to BA definition, depending on the magnitude of the deviation of the latter from the population standard. At the same time, if the 1st rank corresponds to a sharp deceleration, and the 5th — to sharply accelerated ageing, then the 3rd rank reflects the approximate correspondence of the individual value of BA to the population standard [6]. The conducted researches based on the simplified V. P. Voytenko [1] method at large industrial enterprises allowed the authors to reveal a good correlation between BA and nosological (clinical) assessments of the health state [5, 6, 7].

Thus, for BA determination researchers use different sets of 5 to 15 parameters (battery tests). But it is noted [1] that the scheme of aging evaluations does not depend on the choice of tests and includes the following steps:     1) calculation of the actual BA value for the given individual (based on the set of clinical and physiological parameters); 2) calculation of the proper BA value for this individual (by its calendar age (CA)); 3) comparison of the actual and proper values (by how many years or how many times the subject is ahead of their peers or lags behind them according to the rate of aging). This approach allows ranking individuals of one CA according to the degree of age-related wear and tear and, respectively, the health reserve.

The studies of a number of authors have shown that it is sufficiently informative to use shorter battery tests without an instrumental survey for a dynamic study of a large cohort of subjects or for an integrated assessment of workers’ health at periodic reviews.

Materials and methods. The study included 186 agricultural workers with acute pesticide poisoning occurred in industrial conditions as a result of a violation of hygiene regulations. Of these 46 were with acute poisonings with organophosphorus pesticides (OPs), 8 — with synthetic pyrethroids (SPs), 132 — with 2,4-dichlorophenoxyacetic acid (2,4-D)-based herbicides, as well as 62 patients with chronic intoxication with pesticides (CIP) caused by the long-term effects of the pesticide complex, and 60 — apparently healthy individuals (30 women and 30 men). In all of the subjects with acute pesticide poisoning, there was a toxic lesion of the nervous system, and in 92 of the 186 affected (49.5 %), the damage to the nervous system was combined with the development of toxic hepatitis, which was manifested either in the first week of acute poisoning, or in 6–12 months. Toxic hepatitis with the predominance of the cytolytic syndrome was diagnosed in 28 out of 46 patients with acute OPs poisoning (60.9 %), in all 8 cases with acute SPs poisoning and in 56 of 132 patients with acute poisoning with 2,4-D-based herbicides (42.4 %). Among 62 patients with chronic intoxication with pesticides, in all cases, damage to the nervous system in the form of toxic encephalopathy prevailed, which in 52 cases (83.9 %) was combined with toxic hepatitis with a predominance of the cytolytic syndrome. All the subjects were aged 46 to 58 years. The professional composition of patients with the acute poisoning of OPs and SPs was presented by horticulturists-winegrowers, and with poisoning with 2,4-D-based herbicides — beet growers. All patients with acute poisoning were women. Patients with chronic intoxication with pesticides were mostly men, workers at chemical pesticide warehouses, as well as tobacco workers and machine operators.

BA was determined using V. P. Voytenko method, option 4 [1,2]. At the same time, the following tests were recommended by the author for BA screening in women: arterial pulse pressure (APP) is the difference between systolic and diastolic pressure, body weight in light clothing without shoes, health self-assessment index (HSA) [1.2], static balancing (SB) on the left leg (mean value after 3 attempts).

The following recommended tests were used for men to determine BA in outpatient settings: arterial systolic pressure (ASP), breath holding after full inspiration (HFI), health self-assessment index (HSA), and statistical balancing (SB).

BA was calculated in accordance with the formulas proposed by the authors validated by means of multiple linear regression:

For women, BA = – 1.46 + 0.42 x APP + 0.25 x BW + 0.70 x HSA – 0.14 x SB
For men BA = 27.0 + 0.22 x ASP – 0,15 x HFI + 0.72 h HSA - 0,15 x SB

With the above formulas, the valuesof the individual BA (IBA) are calculated for each subject. In order to determine which degree of ageing corresponds to the CA of the subject, IBA was compared with the proper BA (PBA), which characterizes the population standard. PBA was calculated according to the formulas proposed for option 4 [1,2]:

For women, PBA = 0.58 x CA + 17.3
For men PBA = 0.63 х CA + 18.6

For the paired comparison of IBA and PBA parameters, Student’s t-test was used with the software package Stat Soft10.

Study results and their discussion. The table shows IBA and PBA ratios in apparently healthy people and patients with acute poisoning with OPs, SPs and 2,4-D-based herbicides, as well as in patients with chronic intoxication with pesticides. From the table, it is clear that in the group of apparently healthy persons, the ratio of average BA individual and proper values is practically no different from 1 (ageing rate corresponds to the population standard), with the indices for women and men insignificantly different. In patients with acute poisoning with OPs without toxic hepatitis syndrome, IBA was higher than PBA by 2–6 years, and the average IBA and PBA ratio was by 64.4% higher than that of apparently healthy individuals — 0.98 and 1.52, respectively. IBA was even higher in the group of patients with acute poisoning with OPs with toxic hepatitis syndrome. It can be seen from the table that if in apparently healthy people IBA to PBA ratio was 0.98 ± 0.05, then in patients with acute poisoning with OPs with toxic hepatitis syndrome it was 1.64 ± 0.03 (p≤0.05). This parameter in the group of patients with acute poisoning with OPs with toxic hepatitis syndrome not only significantly differed from the parameters in the group of apparently healthy persons, but was significantly different from those in patients with poisoning with OPs without toxic hepatitis syndrome.

Table. Parameters of correlation between individual and proper biological age (IBA/PBA) in patients with acute and chronic intoxication with pesticides (M ± m)

Notes: numerator — IBA/PBA for women, denominator — parameter for men. OPs — organophosphorus pesticides, SPs — synthetic pyrethroids, 2,4-D — herbicides based on 2,4-dichlorophenoxyacetic acid;
* — at р ≤ 0.05 in comparison with apparently healthy people; ** — at p ≤ 0.05 in comparison with patients without toxic hepatitis syndrome.

In the groups of patients with acute poisoning with SPs and 2,4-D-based herbicides, increase in BA was less pronounced (by 2–3 years), although IBA and PBA ratios were significantly higher than those in the group of apparently healthy individuals, especially in patients with toxic hepatitis syndrome. The table shows that the highest rate was in the group of patients with chronic intoxication with pesticides with toxic hepatitis syndrome and was 1.66 ± 0.02, which is significantly higher not only compared to the group of apparently healthy persons, but also to the group with chronic intoxication with pesticides without toxic hepatitis syndrome (р≤0.05).

Thus, BA index may serve as an integral parameter of health status and adequately reflect the severity of the pathological process in acute and chronic intoxication with pesticides. There is a particularly pronounced increase in IBA to PBA ratio in patients with acute and chronic intoxication with pesticides, in the clinical picture of which toxic hepatitis was diagnosed, reflecting a higher rate of ageing or age-related wear and tear of the body.



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