- Email: [email protected]
Pesticides and public health in Brazil
Journal Pre-proof Pesticides and public health in Brazil Francisco J.R. Paumgartten PII:
S2468-2020(20)30005-X
DOI:
https://doi.org/10.1016/j.cotox.2020.01.003
Reference:
COTOX 236
To appear in:
Current Opinion in Toxicology
Received Date: 21 December 2019 Accepted Date: 7 January 2020
Please cite this article as: F.J.R. Paumgartten, Pesticides and public health in Brazil, Current Opinion in Toxicology, https://doi.org/10.1016/j.cotox.2020.01.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier B.V. All rights reserved.
Pesticides and public health in Brazil Francisco J.R. Paumgartten Addresses National School of Public Health, Oswaldo Cruz Foundation, Laboratory of Environmental Toxicology. Av. Brasil 4036, Rio de Janeiro, RJ 21040-361, Brazil. [email protected]
1
Abstract Brazil is one of the world’s top-four agricultural pesticide-consuming countries. The extensive use of pesticides raises concerns about the consequences for the human health. This review appraised the evidence provided by epidemiological studies on the adverse health effects of pesticides conducted in Brazil within the past 2 to 4 years. Available data come from ecological, crosssectional and case-control studies which are relatively easy, quick and inexpensive to conduct, but of limited usefulness for inferring causation and to identify hazards in pesticide risk assessment. Inaccurate exposure assessment is another weakness common to these studies. No longitudinal cohort investigation of pesticide adverse health effects and no analytical data-based biomonitoring study were found in the literature.
In conclusion, studies
conducted in Brazil failed to generate data relevant for risk assessment and management of pesticides. Large prospective cohorts studies and good analytical data on exposures are needed to bridge this public health research gap Key words: Pesticides, cancer, mental disorders, acute poisoning, risk assessment.
2
1.
Introduction In the mid-20th century, the introduction of new, high-yielding varieties of
food crops, and the widespread adoption of mechanization, irrigation techniques and other agricultural technologies resulted in dramatic gains in the production of grains (wheat, maize, soybean and others), particularly in developing countries. This unprecendented increase in cropland productivity (“Green Revolution”) is thought to have changed dramatically the geography of hunger averting millions of deaths from famine worldwide. Nonetheless, Green Revolution’s reliance on a massive use of agrochemicals has also raised concerns about the consequences of the extensive use of pesticides for the environment and public health [1]. Brazil is the second largest producer of soybean in the world, and an important producer and exporter of several other commodity crops as well. Pesticide use considerably increased in tandem with marked rises in the production of grains, and Brazil has become one of the world’s top-four pesticide consumers (together with the US, EU and China) [2]. Recent surveys consistently confirmed that farmers seldom wear appropriate Personal Protective Equipment (PPE) when handling, mixing and applying plant protection products [3-10], a finding that adds to current concerns about the health consequences of country’s consumption of pesticides for agricultural workers. Agricultural commodities are one of the mainstays of Brazil’s economy and pesticide benefits for crop protection must be properly balanced against their potential risks for the environment and human health. Reliable scientific
3
data are necessary to put the estimated burden of diseases associated with pesticide use on one of the dishes of the balance. What is the morbidity and mortality associated with the extensive use of agricultural pesticides in Brazil? Which active ingredients currently used in the country’s agriculture are the most dangerous and should be phased out? What public health interventions could lead to a consistent reduction in the burden of diseases attributable to pesticides? These
questions
have
remained
largely
unanswered
so
far.
Epidemiological studies focusing on them are needed for evidence-based public health interventions intended to reduce the burden of disease associated with the current use of pesticides in Brazil. This article appraised the evidence provided by recent studies which addressed directly or indirectly these research gaps. Epidemiology in health risk assessement of pesticides Epidemiology is one of the cornerstones of Public Health providing data on the distribution of disease in a population (descriptive epidemiology) and on the relationships between exposures and health outcomes within specific populations (analytic epidemiology). Analytic epidemiology approaches test hypotheses on determinants of disease (risk factors) by interventional (clinical trials) and observational investigations. Owing to ethical constraints, hipotheses on the health harms caused by pesticides are generally investigated by observational studies, including longitudinal (retrospective or prospective) cohort studies, case-control comparisons and cross-sectional studies. Analytic studies measure the strength of associations between exposure and diseases, or other adverse health outcomes, in a population at a given time.
4
In pesticide risk assessment (RA), epidemiology contributes to the identification of potential health hazards, assessment of dose-response relationships, and exposure assessment [3,11]. As far as hazard identification is concerned, epidemiological research has the advantage of circumventing uncertainties involved in extrapolating findings from in vitro assays and animal experiments to humans. Nonetheless, association (or correlation) does not necessarily imply causation, and thus non-causal explanations for observed associations should be excluded before concluding that they are likely to be causal. In 1965, a seminal article by Bradford Hill [12] listed nine aspects that should be considered before concluding that causation is a probable explanation for the association. The strength of the association is at the top of Hill’s list. According to Doll [13], when relative risks are small (of the order of 2:1 or less) the problems of eliminating bias and confounding are immense and usually require massive data. Demonstration of a relationship between the magnitude of exposure (dose) and the health outcome incidence or severity (response) also contributes to prove causality. Lack of accurate assessments of pesticide exposure is a pitfall of most observational studies. In complex exposure scenarios as those of agriculture, assessment of exposure is a challenging issue. It is particularly challenging, however, if pesticide exposure is assessed when the health outcome of interest has already occurred, as in case-control and retrospective cohort studies. Studies on the health impact of pesticides Acute pesticide poisonings and pesticide suicides Pesticide poisonings, including self-poisonings (suicides), have been considered a serious public health problem in rural communities of developing
5
countries [4,15-21]. The magnitude of the problem in Brazil, however, remains unclear. Various descriptive studies reported data from surveys performed in some particular regions, or data retrieved from nationwide databases (Notifiable Diseases Information System–SINAN, and National System of ToxicPharmacological Information–SINITOX). There are apparent inconsistencies between reports based on different nationwide databases and one recent study presented clear indications of a significant underreporting of fatal cases of pesticide poisoning [20]. Pesticide exposure and health effect biomarkers A number of cross-sectional studies compared biomarkers of genetic damage (evaluated by comet and cytokinesis-block micronucleus assays, and other tests in lymphocytes and buccal mucosal cells) and/or oxidative stress in Brazilian agricultural workers and individuals not occupationally exposed to pesticides [9,22-25]. These studies, as a rule, concluded that pesticide exposures might result in genetic damage and/or enhanced oxidative stress. A study also described clinical pathology findings in farmers exposed to pesticides [26]. Two cross-sectional studies reported changes in blood levels of thyroid hormone which were inconsistent across sexes and active ingredients [27,28]. The foregoing studies have limitations the most notorious of which were non-random selection of subjects, small sample sizes, inaccurate assessments of pesticide exposure, multiple comparison pitfalls, and lack of a clear and plausible test hypothesis. Pesticide exposure and long term conditions
6
Breast cancer. A case-control study [29] reported that living near of croplands with pesticide application (mostly soybean and corn crops) was associated with a nearly 2-fold increase in breast cancer risk (OR: 2.37; CI 95%: 1.78-3.16). Case–control studies are inexpensive and quick to conduct, and an efficient method for the investigation of rare outcomes. Nonetheless, they suffer from serious limitations including their susceptibility to bias (e.g. recall and selection biases) and reverse causality. In this particular study, the evidence for causality is additionally weakened by an inaccurate assessment of pesticide exposure. The proximity (residing within 500 m) of a pesticide application area was used as a proxy for a quantitative measurement exposure. No data and no previous study, however, were presented to corroborate the underlying hypothesis that dwellers within 500 m of pesticide application areas would be in fact more exposed to this or that pesticide, or to a mixture of active ingredients, than those people who lived outside these arbitrary boundaries. Moreover, the exposure status of case and control women was inferred from responses to questionnaires, and analyzed as a dichotomous variable (exposed/notexposed), yet pesticide exposure (internal doses received by members of a population) is likely to be a continuous variable. In the case of binary variables, nondifferential misclassification might eventually favor the null hypothesis, i.e., it may underestimate hypothetical associations of exposure with health outcomes. Colon cancer (CC). An ecological study raised the hypothesis that pesticide exposure could be a potential risk factor behind a steadily rising incidence of CC in the Southern and Southeast regions of Brazil [30,31]. Ecological studies are descriptive epidemiological approaches that take populations, or groups, as the unit of observation. Being cheap, easy and quick to conduct, they may be
7
useful when individual-level data are either difficult or impossible to collect. A notorious weakness of ecological approaches, however, is that aggregate data are used to assess exposure. Extrapolating conclusions drawn from group results (average in the population) to the individual level may result in interpretation errors (ecological fallacy); i.e., associations observed between group-level variables (e.g., pesticide consumption and CC) do not necessarily exist for particular individuals of the group (i.e., people with CC may not be those who were exposed to pesticides). Owing to its weaknesses, an ecological study provides, at its best, hypothesis-generating information. Conclusions from ecological studies are thus of limited value, if any, for hazard idenfication in RA. Non-Hodgkin lymphoma (NHL). An ecological study reported a correlation between per capita consumption of pesticides and standardized mortality rate by NHL [32]. An additional drawback of this study was that it estimated risks for NHL as an aetiologically related group of malignancies. Nonetheless, NHL encompasses distinct subtypes, and associations of pesticides with NHL seem to be subtype- and compound-specific [33]. Skin melanoma. A pooled analysis of two case-control studies conducted in Italy and Brazil found a higher risk of cutaneous melanoma in individuals occupationnaly exposed to pesticides and sunlight [34]. A previous case-control study in Southern Brazil detected associations between occupational (OR; CI95%: 3.2; 1.2–6.8) and residential (indoors for >10 years; 1.9; 1.2–8.2) exposure to pesticides and cutaneous melanoma [35]. In both studies pesticide exposure was evaluated by a questionnaire. Depressive disorders.
A cross-sectional study found an association of
depressive symptoms (assessed by the Beck Depression Inventory-BDI-II) with
8
pesticide exposure in male farmers (220 coffee growers) from Southeast Brazil [36]. Information about demographic data, life style habits (tobacco, alcohol) and pesticide exposure (yes or no, for any type of pesticide) was assessed by a structured questionnaire applied by trained students and university staff. The multivariate analysis found that pesticide exposure (OR: 5.52; CI95%: 1.18, 25.88), tobacco use (2.81; 1.11, 7.11), poor self-perceived health (2.61;1.33, 5.11) and chronic disease (2.38;1.16, 4.87) were associated with depressive symptoms. Lack of control for possible selection (sampling by convenience instead of random sampling) and information biases seem to be major drawbacks of this study. Another cross-sectional investigation [37] in a rural region of Southern Brazil found associations (OR; CI 50%) between self-reported “pesticide poisoning” and “common mental disorders” (2.63; 1.62-4.25) and “pesticide poisoining” and “depression” (2.62; 1.63-4.21). Shortcomings of this study include multiple comparison pitfalls, inaccurate assessments of exposure and health outcomes (self-reported), and lack of control of potential biases and confoundings. A limitation of cross-sectional approaches for this type of inference is that, unless it can be safely assumed that pesticide exposure was stable over time and was not influenced by the outcome, cross-sectional data are not suitable for drawing conclusions about determinants of chronic conditions, such as psychiatric disorders, cancer, cardiovascular illness, and others, that may have started a long time before associations between exposure and health outcomes were assessed.
9
Male fertility. A cross-sectional investigation in Southern Brazil [38], compared reproductive hormone levels and sperm quality parameters in random samples of young men from rural (n=99) and urban (n=36) areas. Exposure was assessed by questionnaire application. Exposure (lifetime) to pesticides was associated with abnormal sperm morphology and reduced LH and prolactin, while prenatal exposure (reported maternal farming during pregnancy) was associated with larger anogenital distance and testicular volume (measured in adulthood) [38]. Small sample sizes, multiple comparisons and inaccurate assessment of pesticide exposure are major limitations of this cross-sectional study. Concluding remarks. In summary, health effects of occupational exposure to pesticides in Brazil were investigated by ecological, cross-sectional and case-control studies with inaccurate assessments of exposure. Although being relatively easy, quick and inexpensive to conduct, the methodological limitations inherent to these studies hamper causal inferences. To the best of our knowledge, no longitudinal retrospective or prospective cohort study was conducted in Brazil to investigate the health effects of pesticides. Reliable biomonitoring studies and analytical data on pesticide exposures are missing as well. Biomonitoring data are not only an integral part of RA but also needed for a posteriori evaluations of the effectiveness of public health interventions to reduce exposure and risks [39]. In conclusion, epidemiological studies conducted in Brazil – a world’s top pesticide-consuming country – largely failed to generate data relevant for RA of pesticides. The excess of morbidity and mortality attributable to pesticides remains elusive and so does the burden of disease associated with their
10
extensive
use
in
the
country’s
agriculture.
Large
prospective
cohort
investigations are needed to brigde this public health research gap. Obviously, enforcement of strict regulations on the use of PPE and improvement of agricultural and rural extension programs are effective health risk reducing interventions
that
do
not
rely
on
further
epidemiological
data.
11
Conflict of Interest. The author declares no conflict of interest. References 1.
Pimentel D: Green Revolution agriculture and chemical hazards. Sci. Total Environ. 1996, 188 (Suppl.1): S-86-S98.
2.
Donley N: The USA lags behind other agricultural nations in banning harmful pesticides. Environmental Health 2019, 18:44.
3.
Lermen J, Bernieri T, Rodrigues IS, Suyenaga ES, Ardenghi PG: Pesticide exposure and health conditions among orange growers in Southern Brazil. J Environ Sci Health B. 2018; 53(4):215-221.
4.
Magalhães AFA, Caldas ED. Occupational exposure and poisoning by chemical products in the Federal District. Rev Bras Enferm. 2019; 72 (suppl 1):32-40.
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Marcelino AF, Wachtel CC, Ghisi NC. Are Our Farm Workers in Danger? Genetic Damage in Farmers Exposed to Pesticides. Int J Environ Res Public Health. 2019;16(3). pii: E358.
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Ribeiro MG, Colasso CG, Monteiro PP, Pedreira Filho WR, Yonamine M. Occupational
safety
and
health
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among
flower
greenhouses workers from Alto Tietê region (Brazil). Sci Total Environ. 2012; 416:121-6. 7.
Chaves TVS, Islam MT, de Moraes MO, de AlenDeccar MVOB, Gomes DCV, de Carvalho RM, Maluf SW, de Moura do Amaral FP, Paz MFCJ, Cerqueira GS, Rolim HML, de Castro E Sousa JM, de Carvalho MeloCavalcante AA, de Moraes MEA. Occupational and life-style factors-
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acquired mutagenicity in agric-workers of northeastern Brazil. Environ Sci Pollut Res Int. 2017; 24(18):15454-15461. 8.
Brust RS, Oliveira LPM, Silva ACSSD, Regazzi ICR, Aguiar GS, Knupp VMAO. Epidemiological profile of farmworkers from the state of Rio de Janeiro. Rev Bras Enferm. 2019; 72(suppl 1):122-128.
9.
Marcelino AF, Wachtel CC, Ghisi NC. Are Our Farm Workers in Danger? Genetic Damage in Farmers Exposed to Pesticides. Int J Environ Res Public Health. 2019;16(3).
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Cazé AMB, Lacerda ABM, Lüders D, Conto J, Marques J, Leroux T. Perception of the Quality of Life of Tobacco Growers Exposed to Pesticides: Emphasis on Health, Hearing, and Working Conditions. Int Arch Otorhinolaryngol. 2019;23(1):50-59.
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Samet JM, Schnatter R, Gibb H. Epidemiology and risk assessment. Am J Epidemiol. 1998;148(10):929-36.
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Christensen K, Christensen CH, Wright JM, Galizia A, Glenn BS, Scott CS, Mall JK, Bateson TF, Murphy PA, Cooper GS: The use of epidemiology in Risk Assessment: Challenges and opportunities. Hum Ecol Risk Assess 2015; 21(6): 1644-1663.
13.
Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965; 58:295-300.
14.
Doll R.
Proof
of
causality:
deduction from
epidemiological
observation. Perspect Biol Med. 2002; 45(4):499-515. 15.
Hendges C, Schiller ADP, Manfrin J, Macedo EK Jr, Gonçalves AC Jr, Stangarlin JR: Human intoxication by agrochemicals in the region of
13
South Brazil between 1999 and 2014. J Environ Sci Health B. 2019; 54(4):219-225. 16.
Queiroz PR, Lima KC, Oliveira TC, Santos MMD, Jacob JF, Oliveira AMBM.
Notifiable
poisoning
by
Diseases
pesticides
Information in
Brazil.
System Rev
and
Bras
human
Epidemiol.
2019;22:e190033. 17.
Karunarathne A, Gunnell D, Konradsen F, Eddleston M. How many premature deaths from pesticide suicide have occurred since the agricultural Green Revolution? Clin Toxicol (Phila). 2019 Sep 9:1-6.
18.
Buendía JA, Chavarriaga GJR, Zuluaga AF. Burden of paraquat poisoning in the department of
Antioquia,
Colombia. BMC
Pharmacol Toxicol. 2019; 20(1):11. 19.
Gondim AP, Nogueira RR, Lima JG, Lima RA, Albuquerque PL, Veras MD, Ferreira MA. Suicide attempts by exposure to toxic agents registered in a Toxicological Information and Assistance Center in Fortaleza, Ceará, Brazil, 2013. Epidemiol Serv Saude. 2017;26(1):109119.
20.
* Magalhães AFA, Caldas ED. Underreporting of fatal poisonings in Brazil – A descriptive study using data from four information systems. Forensic Sci Int. 2018; 287:136-141. This comparative analysis of notifiable diseases and toxic pharmacological information systems reveals inconsistences between databases and suggests that fatal poisonings are likely to be underreported.
21.
Magalhães AFA, Caldas ED. Two health information systems to characterize poisoning in Brazil-a descriptive study. J Public Health (Oxf). 2019; 41(1):203-211. 14
22.
Benedetti D, Lopes Alderete B, de Souza CT, Ferraz Dias J, Niekraszewicz L, Cappetta M, Martínez-López W, Da Silva J. DNA damage and epigenetic alteration in soybean farmers exposed to complex mixture of pesticides. Mutagenesis. 2018;33(1):87-95.
23.
Claudio SR, Simas JMM, Souza ACF, DO Carmo Baracho DE Alencar M, Yamauchi LY, Ribeiro DA. Genomic Instability and Cytotoxicity in Buccal Mucosal Cells of Workers in Banana Farming Evaluated by Micronucleus Test. Anticancer Res. 2019;39(3):1283-1286
24.
Tomiazzi JS, Judai MA, Nai GA, Pereira DR, Antunes PA, Favareto APA. Evaluation of genotoxic effects in Brazilian agricultural workers exposed to pesticides and cigarette smoke using machine-learning algorithms. Environ Sci Pollut Res Int. 2018;25(2):1259-1269.
25.
Hilgert Jacobsen-Pereira C, Dos Santos CR, Troina Maraslis F, Pimentel L, Feijó AJL, Iomara Silva C, de Medeiros GDS, Costa Zeferino R, Curi Pedrosa R, Weidner Maluf S. Markers of genotoxicity and oxidative stress in farmers exposed to pesticides. Ecotoxicol Environ Saf. 2018;148:177-183.
26.
Dalbó J, Filgueiras LA, Mendes AN. Effects of pesticides on rural workers: haematological parameters and symptomalogical reports. Cien Saude Colet. 2019;24(7):2569-2582.
27.
Piccoli C, Cremonese C, Koifman RJ, Koifman S, Freire C. Pesticide exposure and thyroid function in an agricultural population in Brazil. Environ Res. 2016; 151:389-398
15
28.
Bernieri T, Rodrigues D, Barbosa IR, Ardenghi PG, Basso da Silva L. Occupational exposure to pesticides and thyroid function in Brazilian soybean farmers. Chemosphere. 2019;218:425-429.
29.
* Silva AMC, Campos PHN, Mattos IE, Hajat S, Lacerda EM, Ferreira MJM. Environmental Exposure to Pesticides and Breast Cancer in a Region of Intensive Agribusiness Activity in Brazil: A Case-Control Study. Int J Environ Res Public Health. 2019;16(20). pii: E3951. This is a typical case control control with an inaccurate retrospective assessment of pesticide exposure.
30.
Uyemura SA, Stopper H, Martin FL, Kannen V. A Perspective Discussion on Rising Pesticide Levels and Colon Cancer Burden in Brazil. Front Public Health. 2017;5:273
31.
Martin FL, Martinez EZ, Stopper H, Garcia SB, Uyemura SA, Kannen V. Increased exposure to pesticides and colon cancer: Early evidence in Brazil. Chemosphere. 2018;209:623-631.
32.
Boccolini Pde M, Boccolini CS, Chrisman Jde R, Markowitz SB, Koifman S, Koifman RJ, Meyer A. Pesticide use and non-Hodgkin's lymphoma mortality in Brazil. Int J Hyg Environ Health. 2013;216(4):461-6.
33.
* Leon ME, Schinasi LH, Lebailly P, Beane Freeman LE, Nordby KC, Ferro G, Monnereau A, Brouwer M, Tual S, Baldi I, Kjaerheim K, Hofmann JN, Kristensen P, Koutros S, Straif K, Kromhout H, Schüz J. Pesticide use and risk of non-Hodgkin lymphoid malignancies in agricultural cohorts from France, Norway and the USA: a pooled analysis from the AGRICOH consortium. Int J Epidemiol. 2019; 48(5):1519-1535.
16
This large study presents evidence suggestive that associations of pesticide exposure with NHL may be NHL-subtype and chemical specific.
34.
Fortes C, Mastroeni S, Segatto M M, Hohmann C, Miligi L, Bakos L, Bonamigo
R.
Occupational
Exposure
to
Pesticides
With
Occupational Sun Exposure Increases the Risk for Cutaneous Melanoma. J Occup Environ Med. 2016;58(4):370-5. 35.
Segatto MM, Bonamigo RR, Hohmann CB, Müller KR, Bakos L, Mastroeni S, Fortes C. Residential and occupational exposure to pesticides may increase risk for cutaneous melanoma: a casecontrol study conducted in the south of Brazil. Int J Dermatol. 2015;54(12):e527-38
36.
* Conti CL, Barbosa WM, Simão JBP, Álvares-da-Silva AM. Pesticide exposure, tobacco use, poor self-perceived health and presence of chronic disease are determinants of depressive symptoms among coffee growers from Southeast Brazil. Psychiatry Res. 2018; 260:187192. Illustrate the use a cross-sectional survey to study risk factors of a long-term disorder (depression).
37.
Campos E, Dos Santos Pinto da Silva V, Sarpa Campos de Mello M, Barros Otero U. Exposure to pesticides and mental disorders in a rural population of Southern Brazil. Neurotoxicology. 2016;56:7-16.
38.
Cremonese C, Piccoli C, Pasqualotto F, Clapauch R, Koifman RJ, Koifman
S,
Freire
C.
Occupational
exposure
to
pesticides,
reproductive hormone levels and sperm quality in young Brazilian men. Reprod Toxicol. 2017;67:174-185
17
39.
**
Aylward
LL.
Integration of biomonitoring data
into risk
assessment. Current Opinion in Toxicology.2018, 9:14-20. Interesting analysis of the integration of biomonitoring data into risk assessment and management. The example (figure) of changes in contine concentrations in the US population in 2 time Windows (1988-1991 and 2013-2014) is particularly illustrative of the use of biomonitoring data to assess the effectiveness of public health interventions.
LEGEND TO FIGURE
Figure.
Analytic
epidemiological
approaches
test
hypotheses
on
the
determinants (risk factors) of adverse health outcomes or diseases. Owing to methodological limitations inherent to the study design, it is generally difficult to rule out noncausal explanations for associations dectected by cross-sectional (a snapshot of characteristics of study subjects in a single point in time) and casecontrol studies. Prospective cohort studies (groups based on exposure status followed over time), on the other hand, provide the strongest evidence of causality of observed associations.
18
19
Evidence hierarchy of epidemiological study designs for hazard identification in pesticide risk assessment
Analytic
Prospective cohort studies
Retrospective cohort studies Case-control studies Cross-sectional studies
Descriptive
(with comparison)
Cross-sectional studies (with no comparison)
Ecological studies
Case series Case study / report
Increasing weight of evidence
Conflict of Interest and Authorship Conformation Form Please check the following as appropriate:
o
All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.
o
This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.
o
The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript
o
The following authors have affiliations with organizations with direct or indirect financial interest in the subject matter discussed in the manuscript:
Author’s name Affiliation Francisco José Roma Paumgartten – National School of Public Health – Oswaldo Cruz Foundation
S2468-2020(20)30005-X
DOI:
https://doi.org/10.1016/j.cotox.2020.01.003
Reference:
COTOX 236
To appear in:
Current Opinion in Toxicology
Received Date: 21 December 2019 Accepted Date: 7 January 2020
Please cite this article as: F.J.R. Paumgartten, Pesticides and public health in Brazil, Current Opinion in Toxicology, https://doi.org/10.1016/j.cotox.2020.01.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier B.V. All rights reserved.
Pesticides and public health in Brazil Francisco J.R. Paumgartten Addresses National School of Public Health, Oswaldo Cruz Foundation, Laboratory of Environmental Toxicology. Av. Brasil 4036, Rio de Janeiro, RJ 21040-361, Brazil. [email protected]
1
Abstract Brazil is one of the world’s top-four agricultural pesticide-consuming countries. The extensive use of pesticides raises concerns about the consequences for the human health. This review appraised the evidence provided by epidemiological studies on the adverse health effects of pesticides conducted in Brazil within the past 2 to 4 years. Available data come from ecological, crosssectional and case-control studies which are relatively easy, quick and inexpensive to conduct, but of limited usefulness for inferring causation and to identify hazards in pesticide risk assessment. Inaccurate exposure assessment is another weakness common to these studies. No longitudinal cohort investigation of pesticide adverse health effects and no analytical data-based biomonitoring study were found in the literature.
In conclusion, studies
conducted in Brazil failed to generate data relevant for risk assessment and management of pesticides. Large prospective cohorts studies and good analytical data on exposures are needed to bridge this public health research gap Key words: Pesticides, cancer, mental disorders, acute poisoning, risk assessment.
2
1.
Introduction In the mid-20th century, the introduction of new, high-yielding varieties of
food crops, and the widespread adoption of mechanization, irrigation techniques and other agricultural technologies resulted in dramatic gains in the production of grains (wheat, maize, soybean and others), particularly in developing countries. This unprecendented increase in cropland productivity (“Green Revolution”) is thought to have changed dramatically the geography of hunger averting millions of deaths from famine worldwide. Nonetheless, Green Revolution’s reliance on a massive use of agrochemicals has also raised concerns about the consequences of the extensive use of pesticides for the environment and public health [1]. Brazil is the second largest producer of soybean in the world, and an important producer and exporter of several other commodity crops as well. Pesticide use considerably increased in tandem with marked rises in the production of grains, and Brazil has become one of the world’s top-four pesticide consumers (together with the US, EU and China) [2]. Recent surveys consistently confirmed that farmers seldom wear appropriate Personal Protective Equipment (PPE) when handling, mixing and applying plant protection products [3-10], a finding that adds to current concerns about the health consequences of country’s consumption of pesticides for agricultural workers. Agricultural commodities are one of the mainstays of Brazil’s economy and pesticide benefits for crop protection must be properly balanced against their potential risks for the environment and human health. Reliable scientific
3
data are necessary to put the estimated burden of diseases associated with pesticide use on one of the dishes of the balance. What is the morbidity and mortality associated with the extensive use of agricultural pesticides in Brazil? Which active ingredients currently used in the country’s agriculture are the most dangerous and should be phased out? What public health interventions could lead to a consistent reduction in the burden of diseases attributable to pesticides? These
questions
have
remained
largely
unanswered
so
far.
Epidemiological studies focusing on them are needed for evidence-based public health interventions intended to reduce the burden of disease associated with the current use of pesticides in Brazil. This article appraised the evidence provided by recent studies which addressed directly or indirectly these research gaps. Epidemiology in health risk assessement of pesticides Epidemiology is one of the cornerstones of Public Health providing data on the distribution of disease in a population (descriptive epidemiology) and on the relationships between exposures and health outcomes within specific populations (analytic epidemiology). Analytic epidemiology approaches test hypotheses on determinants of disease (risk factors) by interventional (clinical trials) and observational investigations. Owing to ethical constraints, hipotheses on the health harms caused by pesticides are generally investigated by observational studies, including longitudinal (retrospective or prospective) cohort studies, case-control comparisons and cross-sectional studies. Analytic studies measure the strength of associations between exposure and diseases, or other adverse health outcomes, in a population at a given time.
4
In pesticide risk assessment (RA), epidemiology contributes to the identification of potential health hazards, assessment of dose-response relationships, and exposure assessment [3,11]. As far as hazard identification is concerned, epidemiological research has the advantage of circumventing uncertainties involved in extrapolating findings from in vitro assays and animal experiments to humans. Nonetheless, association (or correlation) does not necessarily imply causation, and thus non-causal explanations for observed associations should be excluded before concluding that they are likely to be causal. In 1965, a seminal article by Bradford Hill [12] listed nine aspects that should be considered before concluding that causation is a probable explanation for the association. The strength of the association is at the top of Hill’s list. According to Doll [13], when relative risks are small (of the order of 2:1 or less) the problems of eliminating bias and confounding are immense and usually require massive data. Demonstration of a relationship between the magnitude of exposure (dose) and the health outcome incidence or severity (response) also contributes to prove causality. Lack of accurate assessments of pesticide exposure is a pitfall of most observational studies. In complex exposure scenarios as those of agriculture, assessment of exposure is a challenging issue. It is particularly challenging, however, if pesticide exposure is assessed when the health outcome of interest has already occurred, as in case-control and retrospective cohort studies. Studies on the health impact of pesticides Acute pesticide poisonings and pesticide suicides Pesticide poisonings, including self-poisonings (suicides), have been considered a serious public health problem in rural communities of developing
5
countries [4,15-21]. The magnitude of the problem in Brazil, however, remains unclear. Various descriptive studies reported data from surveys performed in some particular regions, or data retrieved from nationwide databases (Notifiable Diseases Information System–SINAN, and National System of ToxicPharmacological Information–SINITOX). There are apparent inconsistencies between reports based on different nationwide databases and one recent study presented clear indications of a significant underreporting of fatal cases of pesticide poisoning [20]. Pesticide exposure and health effect biomarkers A number of cross-sectional studies compared biomarkers of genetic damage (evaluated by comet and cytokinesis-block micronucleus assays, and other tests in lymphocytes and buccal mucosal cells) and/or oxidative stress in Brazilian agricultural workers and individuals not occupationally exposed to pesticides [9,22-25]. These studies, as a rule, concluded that pesticide exposures might result in genetic damage and/or enhanced oxidative stress. A study also described clinical pathology findings in farmers exposed to pesticides [26]. Two cross-sectional studies reported changes in blood levels of thyroid hormone which were inconsistent across sexes and active ingredients [27,28]. The foregoing studies have limitations the most notorious of which were non-random selection of subjects, small sample sizes, inaccurate assessments of pesticide exposure, multiple comparison pitfalls, and lack of a clear and plausible test hypothesis. Pesticide exposure and long term conditions
6
Breast cancer. A case-control study [29] reported that living near of croplands with pesticide application (mostly soybean and corn crops) was associated with a nearly 2-fold increase in breast cancer risk (OR: 2.37; CI 95%: 1.78-3.16). Case–control studies are inexpensive and quick to conduct, and an efficient method for the investigation of rare outcomes. Nonetheless, they suffer from serious limitations including their susceptibility to bias (e.g. recall and selection biases) and reverse causality. In this particular study, the evidence for causality is additionally weakened by an inaccurate assessment of pesticide exposure. The proximity (residing within 500 m) of a pesticide application area was used as a proxy for a quantitative measurement exposure. No data and no previous study, however, were presented to corroborate the underlying hypothesis that dwellers within 500 m of pesticide application areas would be in fact more exposed to this or that pesticide, or to a mixture of active ingredients, than those people who lived outside these arbitrary boundaries. Moreover, the exposure status of case and control women was inferred from responses to questionnaires, and analyzed as a dichotomous variable (exposed/notexposed), yet pesticide exposure (internal doses received by members of a population) is likely to be a continuous variable. In the case of binary variables, nondifferential misclassification might eventually favor the null hypothesis, i.e., it may underestimate hypothetical associations of exposure with health outcomes. Colon cancer (CC). An ecological study raised the hypothesis that pesticide exposure could be a potential risk factor behind a steadily rising incidence of CC in the Southern and Southeast regions of Brazil [30,31]. Ecological studies are descriptive epidemiological approaches that take populations, or groups, as the unit of observation. Being cheap, easy and quick to conduct, they may be
7
useful when individual-level data are either difficult or impossible to collect. A notorious weakness of ecological approaches, however, is that aggregate data are used to assess exposure. Extrapolating conclusions drawn from group results (average in the population) to the individual level may result in interpretation errors (ecological fallacy); i.e., associations observed between group-level variables (e.g., pesticide consumption and CC) do not necessarily exist for particular individuals of the group (i.e., people with CC may not be those who were exposed to pesticides). Owing to its weaknesses, an ecological study provides, at its best, hypothesis-generating information. Conclusions from ecological studies are thus of limited value, if any, for hazard idenfication in RA. Non-Hodgkin lymphoma (NHL). An ecological study reported a correlation between per capita consumption of pesticides and standardized mortality rate by NHL [32]. An additional drawback of this study was that it estimated risks for NHL as an aetiologically related group of malignancies. Nonetheless, NHL encompasses distinct subtypes, and associations of pesticides with NHL seem to be subtype- and compound-specific [33]. Skin melanoma. A pooled analysis of two case-control studies conducted in Italy and Brazil found a higher risk of cutaneous melanoma in individuals occupationnaly exposed to pesticides and sunlight [34]. A previous case-control study in Southern Brazil detected associations between occupational (OR; CI95%: 3.2; 1.2–6.8) and residential (indoors for >10 years; 1.9; 1.2–8.2) exposure to pesticides and cutaneous melanoma [35]. In both studies pesticide exposure was evaluated by a questionnaire. Depressive disorders.
A cross-sectional study found an association of
depressive symptoms (assessed by the Beck Depression Inventory-BDI-II) with
8
pesticide exposure in male farmers (220 coffee growers) from Southeast Brazil [36]. Information about demographic data, life style habits (tobacco, alcohol) and pesticide exposure (yes or no, for any type of pesticide) was assessed by a structured questionnaire applied by trained students and university staff. The multivariate analysis found that pesticide exposure (OR: 5.52; CI95%: 1.18, 25.88), tobacco use (2.81; 1.11, 7.11), poor self-perceived health (2.61;1.33, 5.11) and chronic disease (2.38;1.16, 4.87) were associated with depressive symptoms. Lack of control for possible selection (sampling by convenience instead of random sampling) and information biases seem to be major drawbacks of this study. Another cross-sectional investigation [37] in a rural region of Southern Brazil found associations (OR; CI 50%) between self-reported “pesticide poisoning” and “common mental disorders” (2.63; 1.62-4.25) and “pesticide poisoining” and “depression” (2.62; 1.63-4.21). Shortcomings of this study include multiple comparison pitfalls, inaccurate assessments of exposure and health outcomes (self-reported), and lack of control of potential biases and confoundings. A limitation of cross-sectional approaches for this type of inference is that, unless it can be safely assumed that pesticide exposure was stable over time and was not influenced by the outcome, cross-sectional data are not suitable for drawing conclusions about determinants of chronic conditions, such as psychiatric disorders, cancer, cardiovascular illness, and others, that may have started a long time before associations between exposure and health outcomes were assessed.
9
Male fertility. A cross-sectional investigation in Southern Brazil [38], compared reproductive hormone levels and sperm quality parameters in random samples of young men from rural (n=99) and urban (n=36) areas. Exposure was assessed by questionnaire application. Exposure (lifetime) to pesticides was associated with abnormal sperm morphology and reduced LH and prolactin, while prenatal exposure (reported maternal farming during pregnancy) was associated with larger anogenital distance and testicular volume (measured in adulthood) [38]. Small sample sizes, multiple comparisons and inaccurate assessment of pesticide exposure are major limitations of this cross-sectional study. Concluding remarks. In summary, health effects of occupational exposure to pesticides in Brazil were investigated by ecological, cross-sectional and case-control studies with inaccurate assessments of exposure. Although being relatively easy, quick and inexpensive to conduct, the methodological limitations inherent to these studies hamper causal inferences. To the best of our knowledge, no longitudinal retrospective or prospective cohort study was conducted in Brazil to investigate the health effects of pesticides. Reliable biomonitoring studies and analytical data on pesticide exposures are missing as well. Biomonitoring data are not only an integral part of RA but also needed for a posteriori evaluations of the effectiveness of public health interventions to reduce exposure and risks [39]. In conclusion, epidemiological studies conducted in Brazil – a world’s top pesticide-consuming country – largely failed to generate data relevant for RA of pesticides. The excess of morbidity and mortality attributable to pesticides remains elusive and so does the burden of disease associated with their
10
extensive
use
in
the
country’s
agriculture.
Large
prospective
cohort
investigations are needed to brigde this public health research gap. Obviously, enforcement of strict regulations on the use of PPE and improvement of agricultural and rural extension programs are effective health risk reducing interventions
that
do
not
rely
on
further
epidemiological
data.
11
Conflict of Interest. The author declares no conflict of interest. References 1.
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acquired mutagenicity in agric-workers of northeastern Brazil. Environ Sci Pollut Res Int. 2017; 24(18):15454-15461. 8.
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Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965; 58:295-300.
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Doll R.
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Hendges C, Schiller ADP, Manfrin J, Macedo EK Jr, Gonçalves AC Jr, Stangarlin JR: Human intoxication by agrochemicals in the region of
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Queiroz PR, Lima KC, Oliveira TC, Santos MMD, Jacob JF, Oliveira AMBM.
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Gondim AP, Nogueira RR, Lima JG, Lima RA, Albuquerque PL, Veras MD, Ferreira MA. Suicide attempts by exposure to toxic agents registered in a Toxicological Information and Assistance Center in Fortaleza, Ceará, Brazil, 2013. Epidemiol Serv Saude. 2017;26(1):109119.
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* Magalhães AFA, Caldas ED. Underreporting of fatal poisonings in Brazil – A descriptive study using data from four information systems. Forensic Sci Int. 2018; 287:136-141. This comparative analysis of notifiable diseases and toxic pharmacological information systems reveals inconsistences between databases and suggests that fatal poisonings are likely to be underreported.
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Benedetti D, Lopes Alderete B, de Souza CT, Ferraz Dias J, Niekraszewicz L, Cappetta M, Martínez-López W, Da Silva J. DNA damage and epigenetic alteration in soybean farmers exposed to complex mixture of pesticides. Mutagenesis. 2018;33(1):87-95.
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Claudio SR, Simas JMM, Souza ACF, DO Carmo Baracho DE Alencar M, Yamauchi LY, Ribeiro DA. Genomic Instability and Cytotoxicity in Buccal Mucosal Cells of Workers in Banana Farming Evaluated by Micronucleus Test. Anticancer Res. 2019;39(3):1283-1286
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Tomiazzi JS, Judai MA, Nai GA, Pereira DR, Antunes PA, Favareto APA. Evaluation of genotoxic effects in Brazilian agricultural workers exposed to pesticides and cigarette smoke using machine-learning algorithms. Environ Sci Pollut Res Int. 2018;25(2):1259-1269.
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Hilgert Jacobsen-Pereira C, Dos Santos CR, Troina Maraslis F, Pimentel L, Feijó AJL, Iomara Silva C, de Medeiros GDS, Costa Zeferino R, Curi Pedrosa R, Weidner Maluf S. Markers of genotoxicity and oxidative stress in farmers exposed to pesticides. Ecotoxicol Environ Saf. 2018;148:177-183.
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Dalbó J, Filgueiras LA, Mendes AN. Effects of pesticides on rural workers: haematological parameters and symptomalogical reports. Cien Saude Colet. 2019;24(7):2569-2582.
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Piccoli C, Cremonese C, Koifman RJ, Koifman S, Freire C. Pesticide exposure and thyroid function in an agricultural population in Brazil. Environ Res. 2016; 151:389-398
15
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Bernieri T, Rodrigues D, Barbosa IR, Ardenghi PG, Basso da Silva L. Occupational exposure to pesticides and thyroid function in Brazilian soybean farmers. Chemosphere. 2019;218:425-429.
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* Silva AMC, Campos PHN, Mattos IE, Hajat S, Lacerda EM, Ferreira MJM. Environmental Exposure to Pesticides and Breast Cancer in a Region of Intensive Agribusiness Activity in Brazil: A Case-Control Study. Int J Environ Res Public Health. 2019;16(20). pii: E3951. This is a typical case control control with an inaccurate retrospective assessment of pesticide exposure.
30.
Uyemura SA, Stopper H, Martin FL, Kannen V. A Perspective Discussion on Rising Pesticide Levels and Colon Cancer Burden in Brazil. Front Public Health. 2017;5:273
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Martin FL, Martinez EZ, Stopper H, Garcia SB, Uyemura SA, Kannen V. Increased exposure to pesticides and colon cancer: Early evidence in Brazil. Chemosphere. 2018;209:623-631.
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Boccolini Pde M, Boccolini CS, Chrisman Jde R, Markowitz SB, Koifman S, Koifman RJ, Meyer A. Pesticide use and non-Hodgkin's lymphoma mortality in Brazil. Int J Hyg Environ Health. 2013;216(4):461-6.
33.
* Leon ME, Schinasi LH, Lebailly P, Beane Freeman LE, Nordby KC, Ferro G, Monnereau A, Brouwer M, Tual S, Baldi I, Kjaerheim K, Hofmann JN, Kristensen P, Koutros S, Straif K, Kromhout H, Schüz J. Pesticide use and risk of non-Hodgkin lymphoid malignancies in agricultural cohorts from France, Norway and the USA: a pooled analysis from the AGRICOH consortium. Int J Epidemiol. 2019; 48(5):1519-1535.
16
This large study presents evidence suggestive that associations of pesticide exposure with NHL may be NHL-subtype and chemical specific.
34.
Fortes C, Mastroeni S, Segatto M M, Hohmann C, Miligi L, Bakos L, Bonamigo
R.
Occupational
Exposure
to
Pesticides
With
Occupational Sun Exposure Increases the Risk for Cutaneous Melanoma. J Occup Environ Med. 2016;58(4):370-5. 35.
Segatto MM, Bonamigo RR, Hohmann CB, Müller KR, Bakos L, Mastroeni S, Fortes C. Residential and occupational exposure to pesticides may increase risk for cutaneous melanoma: a casecontrol study conducted in the south of Brazil. Int J Dermatol. 2015;54(12):e527-38
36.
* Conti CL, Barbosa WM, Simão JBP, Álvares-da-Silva AM. Pesticide exposure, tobacco use, poor self-perceived health and presence of chronic disease are determinants of depressive symptoms among coffee growers from Southeast Brazil. Psychiatry Res. 2018; 260:187192. Illustrate the use a cross-sectional survey to study risk factors of a long-term disorder (depression).
37.
Campos E, Dos Santos Pinto da Silva V, Sarpa Campos de Mello M, Barros Otero U. Exposure to pesticides and mental disorders in a rural population of Southern Brazil. Neurotoxicology. 2016;56:7-16.
38.
Cremonese C, Piccoli C, Pasqualotto F, Clapauch R, Koifman RJ, Koifman
S,
Freire
C.
Occupational
exposure
to
pesticides,
reproductive hormone levels and sperm quality in young Brazilian men. Reprod Toxicol. 2017;67:174-185
17
39.
**
Aylward
LL.
Integration of biomonitoring data
into risk
assessment. Current Opinion in Toxicology.2018, 9:14-20. Interesting analysis of the integration of biomonitoring data into risk assessment and management. The example (figure) of changes in contine concentrations in the US population in 2 time Windows (1988-1991 and 2013-2014) is particularly illustrative of the use of biomonitoring data to assess the effectiveness of public health interventions.
LEGEND TO FIGURE
Figure.
Analytic
epidemiological
approaches
test
hypotheses
on
the
determinants (risk factors) of adverse health outcomes or diseases. Owing to methodological limitations inherent to the study design, it is generally difficult to rule out noncausal explanations for associations dectected by cross-sectional (a snapshot of characteristics of study subjects in a single point in time) and casecontrol studies. Prospective cohort studies (groups based on exposure status followed over time), on the other hand, provide the strongest evidence of causality of observed associations.
18
19
Evidence hierarchy of epidemiological study designs for hazard identification in pesticide risk assessment
Analytic
Prospective cohort studies
Retrospective cohort studies Case-control studies Cross-sectional studies
Descriptive
(with comparison)
Cross-sectional studies (with no comparison)
Ecological studies
Case series Case study / report
Increasing weight of evidence
Conflict of Interest and Authorship Conformation Form Please check the following as appropriate:
o
All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.
o
This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.
o
The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript
o
The following authors have affiliations with organizations with direct or indirect financial interest in the subject matter discussed in the manuscript:
Author’s name Affiliation Francisco José Roma Paumgartten – National School of Public Health – Oswaldo Cruz Foundation