Note: This was written for Open Philanthropy’s Cause Exploration Prize, in response to their prompt for important pollution in low and middle-income countries. Don't be intimidated by the reading time - 32% of it is due to the reference list, and 24% is optional footnotes.

Summary

• Developmental neurotoxicants (DNTs) are chemicals that have an adverse effect on the structure or function of the nervous system due to early-life exposure. Open Philanthropy is aware of lead as an exemplar DNT. I argue Open Phil should target other DNTs that are widespread, potent, neglected, and tractable.
• The weight of evidence suggests prenatal exposure to organophosphate pesticides is associated with a decrease in the IQ of children. Large numbers of pregnant women in low and middle-income countries may have sufficient organophosphate exposure to produce cognitive deficits in their children. Banning some or all organophosphate pesticides in low-and-middle-income countries could reduce the loss of IQ and so improve wellbeing, and appears cost-effective.
• Accelerating testing to identify unknown developmental neurotoxicants is speculative, but could confer significant value cost-effectively.
• Mercury, polybrominated diphenyl ethers, and arsenic all have fertile research questions that could direct action.

Acknowledgements

Thanks to Dr. Peter Morris, Clare Donaldson, Judith Rensing, Sam Hilton, and Tony Senanayake for helpful comments, advice, and encouragement, though all errors are my own. Thanks especially to Bailey Coleman, Dr. Megan McHenry, and their team for early access to their draft of “Pesticides and neurodevelopment of children in low and middle-income countries: a systematic review”.

Introduction

Developmental neurotoxicants (DNTs) are chemicals with an adverse effect on the structure or function of the nervous system due to early-life exposure.^[1] Because they affect lifelong IQ and thus lifetime earnings, DNTs have cost trillions in value globally.^[2] Lead is an important example, which Open Philanthropy is already aware of. I claim Open Phil should expand to work on other DNTs that are widespread, potent, neglected, and tractable.

I focus here on organophosphate pesticides. I also analyse increased effort to find unknown DNTs. I end with key research questions for mercury, polybrominated diphenyl ethers (PBDEs), and arsenic.

Organophosphate pesticides

Organophosphates are a common class of pesticide used mainly as agricultural insecticides (see Wikipedia). Humans become exposed via eating pesticide-treated food, hand-to-mouth behaviour from contaminated surfaces, breathing airborne residues, and skin absorption.^[3]

Some high-income countries (HICs) have been restricting organophosphates since 2001, with greater momentum recently.^[4] Regulation on pollution to protect health in low and middle-income countries (LMICs) has often lagged HICs by decades or more.^[5] I argue we should not let such a lag happen again, but instead accelerate the arrival of regulation of organophosphates for agricultural use in LMICs.

Pesticide bans on suicide-prevention grounds appear to have not affected agricultural yield, and organophosphates are said to have accessible alternatives.^[6] However, pesticide restrictions may have reduced agricultural yield in the past, and individuals in target LMICs may have strong views on whether restrictions are justified. Estimating the potential impact of bans on agricultural yield and livelihoods would be an important component of fuller analysis.

I claim that banning some or all organophosphate pesticides in some LMICs would cause a slight increase in the IQ of a significant number of those countries’ children. I argue the claim in three parts. I then assess importance, neglectedness, and tractability. I perform back-of-the-envelope calculations for three candidate countries, and discuss uncertainties.

The argument

Sufficient prenatal exposure to organophosphate pesticides is associated with the loss of IQ in children

Animal evidence

The unifying mechanism of organophosphates is the inhibition of acetylcholinesterase (AChE), which breaks down the neurotransmitter acetylcholine. This mechanism was the basis for early studies attempting to establish safe organophosphate levels in humans.^[7] However, animal and in vitro models support developmental neurotoxicity of some organophosphates at doses below the threshold of AChE inhibition.^[8] Animal and in vitro models have suggested a surfeit of other mechanisms for the developmental neurotoxicity of organophosphates:^[9]

Human evidence

Epidemiological evidence

Three cohort studies in the U.S. form the foundation of epidemiological evidence.^[10]

Rauh et al. (2011) measured levels of a common organophosphate called chlorpyrifos in the umbilical cord blood plasma in 265 children in New York City.^[11] They tested the children at age 7 and found that each standard deviation increase in chlorpyrifos exposure was associated with a 1.4% decrease in full-scale IQ (FSIQ) (0.94-1.8 points, p = 0.048) and 2.8% decrease in working memory (1.6-3.7 points, p = 0.003), with no interaction between this effect and any of the demographic variables or measures of other chemical exposures.

Organophosphates break down into metabolites called dialkyl phosphates (DAPs), which can be measured in urine as a marker of organophosphate exposure. Bouchard et al. (2011) measured DAPs in pregnancy and then tested the resulting 329 children at age 7.^[12] They found that each 10-fold increase in prenatal DAP was associated with a loss of 5.3 points on FSIQ (-8.6 to -2.0, p = 0.01), significant for all subcomponents (working memory, processing speed, verbal comprehension, perceptual reasoning). Rowe et al. (2016) re-assessed the same cohort at age 10, but measured exposure using the California Pesticide Use Reporting system.^[13] The independent difference between the highest and lowest quintile of prenatal proximal pesticide use was a deficit of 4 IQ points.

Engel et al. (2011) measured maternal DAPs and assessed 169 children at 6-9 years of age. They found decrements in FSIQ and other indices, but these effects were modest, imprecise, and specific to particular DAP subsets.

Bellinger (2012) weighted the two studies relating maternal urinary DAP to childhood FSIQ by sample size.^[14] He suggests an effect size of -4.25 IQ points for a 10-fold increase in maternal urinary total DAP, with an assumption of no effect under 50 nmol/L and a ceiling of -4.25 points above 500 nmol/L.

According to the European Chemicals Agency, 28 additional epidemiological studies performed since 2017 are “in line with the remaining body of evidence but do not provide significant new information”.^[15]

Systematic reviews

A 2019 systematic review concluded there was considerable evidence that organophosphate pesticides negatively affect neurodevelopment, while noting controversy.^[16] 45/50 studies found an association. 22/24 studies (n = 6637) on school-aged children found a significant negative neurodevelopmental effect, with 14 studies being cohort-based.

This summary was concordant with three earlier systematic reviews.^[17] In addition, Munoz-Quezada et al. 2013 looked at studies assessing dose-response relationships, and reported that 11/12 found a significant dose-response. 10 longitudinal studies based on 3 birth cohorts found prenatal organophosphate exposure had a dose-response relationship with cognitive deficits in children aged 7, behavioural deficits in toddlers, and motor deficits in neonates. The diversity of outcome measurements precluded Munoz-Quezada et al. from conducting a meta-analysis.

A meta-analysis by an Iranian group found a significant effect of prenatal occupational organophosphate exposure on children’s cognition (figure below), although it was based on only two studies after excluding a third.^[18]

According to a draft of a systematic review to be published this year, 19/26 studies in LMICs found a significant negative effect between pesticide exposure and at least one neurodevelopmental domain.^[19] Three questionnaire-based assessments of maternal exposure including organophosphates associated cognitive deficits with pesticide use in Tanzania and Ecuador.^[20]

Other subsequent evidence

Below is a summary of other studies assessing neurocognitive effects of prenatal organophosphate exposure published after the most recent systematic review:

Indirect evidence

Ross et al. (2012) conducted a systematic review and meta-analysis of occupational studies assessing long-term, low-level exposure to organophosphates without acute intoxication in adults. They found 14 studies (n = 1600) and a significant association with impaired neurocognitive function.

Ramirez-Santana et al. (2020) assessed adults in Chile. They found that long-term exposure (>10 years) to organophosphate or carbamate pesticides without any acute intoxication predicted poorer neurobehavioral impairment in adults, with the effect increasing during the spraying season.

Expert opinion

Expert opinion bolsters the conclusion that organophosphates are likely DNTs.

The European Food Safety Authority concluded in 2019 that prenatal organophosphate exposure consistently produces cognitive and behavioural deficits.^[21]

The U.S. EPA concluded in 2016 that epidemiological evidence was sufficient to conclude that chlorpyrifos was causing neurodevelopmental effects at concentrations below the level of AChE inhibition.^[22]

An expert panel used a method from the Intergovernmental Panel on Climate Change, and suggested the probability range for a causal relationship between organophosphates and loss of IQ was 70-100%.^[23] They rated the toxicological evidence ‘strong’ and the epidemiological evidence ‘moderate-high’.

A substantial number of pregnant women in some LMICs have significant exposure to organophosphate pesticides

Cognitive deficits from organophosphate exposure are likely significant in HICs.^[24] LMICs tend to have a larger rural population, less regulation of pesticides, less-informed applicators, and more nutritional deficiencies (which exacerbate pesticide effects).^[25]

In addition to diet, women living in agricultural areas can be exposed occupationally, para-occupationally, residentially, and through agricultural drift (e.g. windborne from application or residues on plants/soil).^[26]

Data on organophosphate use

Incomplete data suggests that LMICs use a substantial amount of organophosphates, especially in Asia:^[27]

Asia also dominates imports of hazardous pesticides:^[28]

Import and usage data, farmer surveys, chemical analysis of markets, passive environmental sampling, and farmer-worn silicone wristbands all support substantial organophosphate use in Africa.^[29]

A Pesticides Action Network report suggests hazardous pesticide use is widespread in Asian LMICs.^[30]

Exposure in pregnant women in LMICs

Baumert et al. (2022) measured 6 serial urinary DAPs in 316 pregnant women in rural Thailand, and found higher levels than those in the U.S. cohort studies:

Kongtip et al. (2013) assessed 86 pregnant women in Thailand, only half of whom lived near farmland. They found DAP levels throughout pregnancy to be at least double the minimum assumed by Bellinger for an effect on IQ. Other studies in Thailand are consistent with this level.^[31]

Samples of meconium (a baby’s first stool) in rural Thailand showed organophosphate exposure in 98% of cases.^[32]

For pregnant women in rural Bangladesh, pesticide-specific biomarkers were 3-38X higher than US females.^[33]

A study of 1303 pregnant women in China found ~11X higher median concentrations of a pesticide-specific biomarker compared to a U.S. survey.^[34]

Exposure in other populations in LMICs

A recent comparison showed that exposure measured by DAPs in children in Thailand and Malaysia is comparable to HICs:^[35]

This pattern is consistent with results from China, as well as a review of studies on child labourers in Egypt and Brazil.^[36]

An eight-country comparison from 2006-2014 shows the following for three organophosphates (chlorpyrifos, parathion, and diazinon):^[37]

Li & Kannan (2018) represent the proportion of the population experiencing a daily intake of chlorpyrifos above the hazardous limit:

While I cannot be confident of exhausting the literature, the majority of studies show LMICs to have an equal or greater exposure to organophosphates than the U.S. studies which suggested an effect on IQ.

Banning the problematic pesticides could reduce exposure

A critical piece of future evidence that Open Phil could pursue is a comparative study or randomised-controlled trial to assess whether controls on organophosphates lead to higher IQs in children, though the time this takes should be considered versus the value of information gained.^[38] Whilst there isn’t direct evidence yet that pesticide bans lead to gains in IQ, there is evidence that bans of specific pesticides lead to lower exposure, described next.

The U.N. (2022) says that countries with strict regulations have reduced the effects of organophosphates, although their citations for this claim are about birds.

Food monitoring and human biomonitoring show an abrupt and significant decline in chlorpyrifos exposure following the EU ban in 2016.^[39]Israeli data showed declining DAPs in pregnant women following restrictions of 18 organophosphate ingredients.^[40]

The U.S. phased out chlorpyrifos and diazinon in 2000/01 for residential use. Decreases in exposure have been found in young children’s environment and urine, and prenatal personal air samples.^[41] A NYC cohort found chlorpyrifos exposure halved over ten years, while markers of pesticides that were not banned did not change.^[42]

Organochlorines are a class of pesticide that were banned in the 1970s. Despite being a more persistent class, Li et al. (2022) assess serum organochlorine levels in the U.S. and find declines of around 15% every 2 years. Comparing generations born before and after the bans suggest a drop of 40%.^[43]

A systematic review which found that bans on pesticides reduced pesticide-suicides and overall mortality.^[44] Data in Sri Lanka showed that bans on specific pesticides reduced their use in pesticide-suicides substantially.^[45]

Importance

Gaylord et al. (2020) estimate that from 2001-2016 organophosphates were responsible for the loss of >26 million IQ points, which due to the expected loss in lifetime earnings results in a cost of around $735 billion, or $46B/year. Similarly, Attina et al. (2016) estimate that cognitive deficits due to organophosphates cost the U.S. $44.7B/year, or 0.3% of GDP.

Bellanger et al. (2015) estimate that organophosphate-caused cognitive deficits cost the E.U. $194B (sensitivity: $62B-$259B) annually, or 1.14% of GDP.^[46]

The combined GDP of LMICs is $36.32 trillion.^[47] If organophosphates were affecting LMICs to a similar extent as the U.S., the cost of organophosphates to LMICs would be $108B/year. If similar to the EU, the cost to LMICs would be $414B/year.

Given higher agricultural employment rates and rural population size, a relative lack of pesticide regulation, and unsafe pesticide practices, it would be reasonable to expect organophosphates to be an even larger problem for LMICs than for the U.S./E.U.

A more formal estimate of the cost to LMICs with quantified uncertainty is beyond the scope of this paper, though could be a useful project. Note that the above estimates are smaller than the annual cost of cognitive deficits caused by lead in LMICs (~$1 trillion), arrived at by similar methods and authors.

I quantify estimates of the ‘units of value’ lost due to the decline in IQ for three case studies in the BOTEC section.

Neglectedness

Political

According to the Lancet Commission, global response to pollution-caused ill-health since 2017 has been weak.^[48]

The Strategic Approach to International Chemicals Management (SAICM) is the only comprehensive process targeting chemical pollution.^[49] It intended to explore a global action plan on highly hazardous pesticides (HHPs) at its next 5-yearly conference in 2021, but that meeting has been postponed indefinitely.^[50] There is no mechanism for the global action plan, and a government representative from Africa stated that “Most LMICs lack the knowledge and capacity to implement.”^[51] Involvement in SAICM is voluntary, and its total 2022 budget was $5.9M.^[52]

Even the labelling of hazardous substances has seen little activity, with no implementation commitments made in 1992 by 120 countries including all of Africa (except Zambia) and all of South Asia.^[53]

The Global Environment Facility, a critical source of finances in environmental work, focuses almost exclusively on Persistent Organic Pollutant (POP) pesticides under the Stockholm Convention.^[54] POPs are chemicals that are toxic, persist in the environment for years, and accumulate in food chains. Chlorpyrifos is being considered for inclusion, but most organophosphates are unlikely to be included in the near-term future.^[55]

I found information for one BOTEC case, the Philippines, for the technical regulatory agency in charge of pesticides.^[56] In 2023 its budget for regulation was $1.6M.^[57]

Academic

83% of occupational exposure studies for pesticides occur in high or upper-middle income countries, with only 1.1% from low-income countries.^[58] Key research gaps concern both developmental neurotoxicity and risks to pregnant/nursing women and young children.^[59]

The Global Burden of Disease project only assesses factors with detailed data on both exposures and outcomes, and where there is strong evidence of causation.^[60] As such, they do not include estimates of the global burden due to pesticides, let alone organophosphate pesticides.^[61] However, the GBD authors note global exposure to pesticides would be important to include in the future, if data were available.^[62]

Civil society

ToxicsLink is the South Asia coordinator for the International Pollutants Elimination Network ToxicsLink has total assets of ~US$539K, with their Chemicals focus area including lead, POPs, and mercury.^[63]I’d guess less than $100K is spent on non-POP pesticides.

The Pesticide Action Network (PAN) appears to be the largest NGO group working on pesticides globally.^[64] Their scientific grounding and risk of bias appears questionable, exemplified by their campaigns against genetically-modified organisms, or merging surveys with advocacy to participants. Combined, PAN’s global assets appear to be less than $4M.^[65] I’d guess less than $1M is spent on LMIC regions.

The Center for Pesticide Suicide Prevention (CPSP) works with national governments in Asia and Africa to determine what pesticides are being used most in suicides, and then try to deregister them.^[66] In 2021, GiveWell recommended a $7M grant from Open Philanthropy for CPSP’s costs for three years.^[67] They appear well placed to work on reducing DNT pesticide exposure. However, despite overlap with their suicide-prevention work, tackling DNT pesticides would significantly alter CPSP’s activities in four ways:

1. New pesticides: Targeting DNT pesticides would substantially add to the list of pesticides CPSP tries to deregister. CPSP list Sri Lanka, China and Bangladesh as countries that have significantly reduced their pesticide-suicide burden. Sri Lanka has only banned 11/41 organophosphates, China 16, and Bangladesh 5.^[68] Thus reductions of pesticide-suicides do not always result in degregistration of organophosphates. 36.5% of organophosphates are not listed as HHPs, and only 18% of HHPs are organophosphates, suggesting that future HHP deregistrations will only partly reduce DNT burden.

2. New countries:
   Cost-effectiveness of pesticide-suicide prevention drops as the burden of pesticide-suicide decreases.^[69] Targeting DNT would lead to new countries becoming cost-effective targets for the CPSP, such as the Philippines and Nigeria.

3. New advocacy tools:
   Tackling DNT would expand and strengthen arguments for specific pesticide deregistration, enhancing CPSP’s work with governments.

4. New cost-effectiveness estimates:
   Tackling DNT would increase CPSP’s already impressive cost-effectiveness estimates, and make them more conceptually and empirically robust.

Tractability

One aspect of tractability concerns whether regulation targets single organophosphate pesticides or the whole class. Heterogeneity in the preclinical literature and DNT effects below the level of AChE-inhibition suggest the possibility that not all organophosphates are DNTs.^[70] However, pesticide-specific evidence is limited by available data and a lack of specific exposure measures.^[71]

Gunier et al. 2017 used California’s reporting system to estimate pesticide-specific effects, finding variable but large DNT effects for four separate organophosphates. 26/41 organophosphates are already considered highly hazardous (HHPs) by the FAO-WHO. Of the 15 non-HHP organophosphates, a cursory literature search found implications of developmental neurotoxicity for 9.^[72] This evidence may be weak or wrong, but my impression is that a precautionary approach could justify a whole-class ban on organophosphate pesticides, and this has been recommended in the literature.^[73]

A modest goal would be to regulate organophosphates in LMICs to the same degree as the E.U. and U.S. The current regulatory situation is summarised here.^[74] 18/41 organophosphates have been withdrawn from registration in the U.S.; the E.U. has banned 26. Relevant LMIC precedent is set by China (16 banned) and Indonesia (21 banned). In my BOTEC cases, the Philippines has banned 2, and Bangladesh and Nigeria have both banned 5.

Targeted pesticide deregistrations have occurred in LMICs in the past, and GiveWell assesses the CPSP to have a good chance of success (30%-60%) in several Asian countries for deregistring pesticides on suicide-prevention grounds.^[75]

There would be synergy between action on HHPs and DNT-relevant pesticides. The postponed SAICM conference will explore the execution of the Global Action Plan, while an alliance for HHP action is beginning to be designed.^[76] The next 1-3 years could be pivotal to getting DNT on the agenda for global pesticide action.

While industry appears supportive of work on HHPs, they may be resistant to organophosphate regulation.^[77] Assessing potential pushback/inertia would be an important part of a thorough assessment of this intervention.

Back of the envelope calculations

I conducted BOTECs for the Philippines, Bangladesh, and Nigeria, here. They should not be taken literally, but are illustrative of the area’s potential.

Inputs

Each section has an explanatory note in the spreadsheet. The section on organophosphate burdens is complicated, so its note is below.

Organophosphate burden

A comparator country with organophosphate exposure data is Thailand. Baumert et al. (2022) studied 330 pregnant women in two rural communities in northern Thailand, with the region chosen for generalisability to other LMICs. The table below shows results converted into nmol/L:

These figures are consistent with results from earlier, smaller studies in Thailand.^[78]

Compared to Thailand, the Philippines is poorer, more rural, and imports more hazardous pesticides. Assuming their organophosphate burden is similar to Thailand is a conservative assumption.

Similar reasoning applies to Bangladesh. Pesticide-specific biomarkers in pregnant women in Bangladesh were many times higher than U.S. comparators.^[79] Spotty data on organophosphate usage suggest broad comparability (such data is unavailable for Philippines/Nigeria):

Although both are trending down, the Baumert et al. (2022) samples (collected 2017-2019) suggest that significant exposure remains.

As further corroboration, the incidence of acute unintentional pesticide poisonings in agricultural populations may be a proxy of unsafe pesticide practices and prevalence of toxic pesticides. The incidence in Thailand is 36%, while the Philippines and Bangladesh are 57.99% and 55.64% respectively.^[80]

Nigeria is the least certain case. Nigeria has a higher incidence of acute unintentional pesticide poisonings than both South Africa and Thailand.^[81] Urinary DAPs in women in South Africa were substantially higher than the U.S. and E.U., and pesticide-specific biomarkers were higher than Bangladesh. A conservative assumption is that Nigeria’s organophosphate exposure is similar to Thailand/Bangladesh.

60 nmol/L is the level at which a 20% reduction (the highest reduction I consider) remains above the 50 nmol/L cut-off for a DNT in the literature. Based on a normal distribution on the Baumert data, ~70% of the rural population are above 60 nmol/L.

Results

For the Philippines, my conservative model suggests a $450,000 program regulating organophosphates could be 42X as cost-effective as GiveDirectly. Such a program would need to reduce exposure by 1.35% to still be at least 10X as cost-effective as GiveDirectly (a rough funding threshold). If the program reduced exposure by 4%, costs could be as high as $1.3M to still break the ‘10X bar’.

For Bangladesh, my conservative model suggests a $390,000 program would be 90X as cost-effective as GiveDirectly. Such a program would need to reduce exposure by 0.53% to break the 10X bar. It could cost $3.5M and still break the ‘10X bar’.

For Nigeria, my conservative model suggests a $450,000 program would be 66X as cost-effective as GiveDirectly. It would need to reduce exposure by 0.3%, or alternatively cost less than $3M, to still break the ‘10X bar’.

As well as the conservative case for each country, I also made a ‘best-guess’ scenario, seen in the table (open image in new tab due to formatting).

Limitations, reasons I’m wrong, and further questions

Two particularly important sets of limitations

Randomised-controlled trials for organophosphate exposure don’t exist yet. Current epidemiological evidence is limited by ^[82]:

• limited power and precision

• exposure to multiple neurotoxicants, which can confound or combine non-linearly

• needing data on exposures in the prenatal period - DNTs may not persist in the environment long or have specific/reliable markers

• needing data on long-term outcomes, which is expensive, difficult, heterogeneous between studies, and limits sample size.

Much evidence depends on using urinary DAPs, but these are an imperfect guide to organophosphate exposure as they ^[83]:

• aren’t specific to parent pesticides

• lack a dose-response relationship to clinical cholinergic signs/symptoms

• have substantial intra- and inter-day variability

• can have higher within-person than between-person variability ^[84]

• have only partial correlation with measured organophosphate doses ^[85]

Seven good reasons to think I’m wrong

• The estimated effect size is based on only 2 longitudinal studies, with a combined sample size of 498. While systematic reviews suggest the effect is supported by subsequent literature, the effect size has not been recalculated based on new data - and the true value may be significantly different.

• The average expected IQ gains per child appears small on the BOTEC (partly due to adjustments for effect size, likelihood of effect being real, and modest assumptions of regulatory impact). The small differences become important because of the large populations affected. But it’s unclear if such small differences would be either detectable on neuropsychological testing or impactful for future earnings/wellbeing.

• The agricultural impact of restricting organophosphates is probably bigger than HHPs - so the possible negative effects are higher and it may be more politically difficult (modelled in BOTEC as 40% adjustment, compared to a 70% adjustment used in GiveWell’s CPSP BOTEC).

• The theory of change is long and uncertain. Here’s a simplistic linear schematic:
  funded intervention → bans/deregistrations → less organophosphate use → less organophosphate exposure in pregnant women → improved neurodevelopment of children → increased lifetime earnings → increased lifetime wellbeing.
  90% confidence in each arrow results in a conjunctive probability of 53%.^[86]

• A lot of work estimating the economic impact of developmental neurotoxicants uses similar methods and is conducted by similar groups of academics; this literature might be misguided or biased in particular ways, which this analysis doesn’t consider critically.

• I use the GiveWell conversion of 0.22 units of value for each IQ point gained from their BOTEC for Pure Earth, and don’t interrogate it.^[87] But this is a key part of estimating this intervention’s benefits, and could be questioned on normative and empirical grounds.^[88]

• While I have training in neuroscience and medicine, I am not a toxicologist, agriculturalist, or public health professional. I can’t be confident my summary of the literature is comprehensive.

Eleven questions

• What is the expected loss of IQ points and earnings due to organophosphate pesticide exposure in LMICs?

• Would regulation of organophosphates lead to higher child IQs in LMICs?

• What is the expected impact of organophosphate restrictions on agricultural yield in LMICs?

• How do the benefits of use of organophosphates for malaria control compare to potential DNT effects? Are there viable alternatives?

• What is the contribution of other sources of organophosphate exposure, such as flame retardants?

• Is there a DNT risk from other pesticide classes? ^[89]

• How much would consideration of DNT change the CPSP’s activities?

• What is the likely effect of HHP-focused activities on DNT burden?

• What is the likely amount of industry resistance? How might it affect strategy?

• What is the likelihood that chlorpyrifos is accepted as a persistent organic pollutant under the Stockholm Convention? What about other DNT-organophosphates?

• What is the true relationship between neurodevelopmental outcomes measured in childhood and lifetime wellbeing?

Finding unknown developmental neurotoxicants

We need to be more proactive and systematic against DNTs. That might mean trying to find currently unknown DNTs. Here’s a speculative sketch of cost-effectiveness for that idea.

Global chemical production has increased 50X since 1950, and will triple again by 2050 relative to 2010.^[90] There are around 350,000 unique chemicals or mixtures on the global market, of which 70,000 have been registered in the past decade.^[91] Of these, nearly 30,000 have only been registered in developing countries.^[92] The only comprehensive testing process is E.U.’s REACH.^[93] Over ten years, REACH has assessed only 20% of end-products with production over 1 ton/year on the European market .^[94] It appears likely that there are thousands of new chemicals being synthesised at high volumes in LMICs which will not be tested for developmental neurotoxicity for decades.

There are 201 known human neurotoxins, with around 2 added each year between 2006 and 2012; around half have high production volumes.^[95] 11 are considered DNTs.^[96] 5 DNTs are synthetic. Assuming independence, the chance of identifying a synthetic, high-production, developmental neurotoxicant within x years is:^[97]
1 - (1 - (0.0248))^x

For 10 years, that chance is ≈22%.

For 20 years, ≈39%.

For 30 years, ≈53%.

I made a BOTEC for a program costing $10M/year for 20 years with the effect of accelerating DNT identification by 10 years^[98]. Such a program could be >40X as cost-effective as GiveDirectly. It would need at least a 25% chance of accelerating detection by 10 years to clear the 10X bar. If we expected a 50% chance of 10-year accelerated detection, it could cost $20M/year - more than the operational expenditure of EU’s REACH^[99] - for 20 years before dipping below the 10X bar. \

Is such an acceleration feasible? It took decades to recognise and restrict currently known synthetic DNTs.^[100] If a synthetic DNT is first identified in 30 years time, it is probably being produced today. Instead of waiting 30 years to identify it, we could accelerate DNT identification compared to the historic record and our current trajectory, given REACH’s limited pace and focus on the European market.^[101] We could leverage new toxicological techniques to scale DNT testing without commensurate increases in animal testing.^[102] We could increase biomonitoring for developmental neurotoxicity in LMICs and better characterise DNT burdens.^[103] We could act faster and more comprehensively when developmental neurotoxicity is suspected. We could prevent history from repeating itself.

This idea requires a much more detailed analysis, but I hope this sketch has suggested that it merits one.

Other developmental neurotoxicants

Space precludes detail on other DNTs, but here are some actionable questions:

• Mercury is a global problem, and a key source is artisanal and small-scale gold mining.^[104] However, there are large programs addressing this already.^[105] Are there neglected, cost-effective opportunities in the space?

• PBDEs cause a significant DNT burden, but are already covered by the Stockholm Convention.^[106] Are there non-regulatory interventions that are scalable and cost-effective for reducing PBDE exposure in LMICs?

• Arsenic’s global harms may be comparable to lead, but there’s a severe lack of data on global exposure and impact.^[106:1] What’s the best estimate of arsenic’s DALY impact? What research is needed? What interventions are feasible?

Conclusion

Developmental neurotoxicants show potential as a focus for Open Philanthropy’s ambition to tackle the most important pollution in LMICs. Lead is an important example with work already being funded. Prenatal exposure to organophosphate pesticides likely decreases the IQ of millions of children in LMICs - accelerating the arrival of regulation could cost-effectively and seems neglected and tractable. Accelerating testing to find currently unknown DNTs earlier is a more speculative intervention, but appears promising. Mercury, PBDEs, and arsenic all have action-guiding research questions which appear fertile for future work.

References

Abreu-Villaça, Yael, and Edward D. Levin. 2017. "Developmental Neurotoxicity Of Succeeding Generations Of Insecticides". Environment International 99: 55-77. doi:10.1016/j.envint.2016.11.019.

Andersen HR, et al. 2015. “Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age”. Neurotoxicol Teratol. 47:1–9.

Attina TM, Hauser R, Sathyanarayana S, Hunt PA, Bourguignon JP, Myers JP, DiGangi J, Zoeller RT, Trasande L. “Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis.” Lancet Diabetes Endocrinol. 2016;4:996–1003. doi: 10.1016/S2213-8587(16)30275-3.

Balaguer-Trias, Jordina, Deepika Deepika, Marta Schuhmacher, and Vikas Kumar. 2022. "Impact Of Contaminants On Microbiota: Linking The Gut–Brain Axis With Neurotoxicity". International Journal Of Environmental Research And Public Health 19 (3): 1368. doi:10.3390/ijerph19031368.

Balalian, Arin A., Xinhua Liu, Julie B. Herbstman, Sharon Daniel, Robin Whyatt, Virginia Rauh, Antonia M. Calafat, Ronald Wapner, and Pam Factor-Litvak. 2021. "Prenatal Exposure To Organophosphate And Pyrethroid Insecticides And The Herbicide 2,4-Dichlorophenoxyacetic Acid And Size At Birth In Urban Pregnant Women". Environmental Research 201: 111539. doi:10.1016/j.envres.2021.111539.

Barr, Dana Boyd, Kurunthachalam Kannan, Yuxia Cui, Lori Merrill, Lauren M. Petrick, John D. Meeker, Timothy R. Fennell, and Elaine M. Faustman. 2021. "The Use Of Dried Blood Spots For Characterising Children's Exposure To Organic Environmental Chemicals". Environmental Research 195: 110796. doi:10.1016/j.envres.2021.110796.

Basu, Niladri, Milena Horvat, David C. Evers, Irina Zastenskaya, Pál Weihe, and Joanna Tempowski. 2018. "A State-Of-The-Science Review Of Mercury Biomarkers In Human Populations Worldwide Between 2000 And 2018". Environmental Health Perspectives 126 (10): 106001. doi:10.1289/ehp3904.

Bellanger M, Demeneix B, Grandjean P, Zoeller RT, Trasande L. 2015 “Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine-disrupting chemicals in the European Union.” J Clin Endocrinol Metab.;100:1256–1266. doi: 10.1210/jc.2014-4323.

Bellinger, David C. 2012. "A Strategy For Comparing The Contributions Of Environmental Chemicals And Other Risk Factors To Neurodevelopment Of Children". Environmental Health Perspectives 120 (4): 501-507. doi:10.1289/ehp.1104170.

Bemanalizadeh, Maryam, Mehri Khoshhali, Parvin Goli, Ibrahim Abdollahpour, and Roya Kelishadi. 2022. "Parental Occupational Exposure And Neurodevelopmental Disorders In Offspring: A Systematic Review And Meta-Analysis". Current Environmental Health Reports. doi:10.1007/s40572-022-00356-6.

Benavides-Piracón, John Alexander, David Hernández-Bonilla, José Antonio Menezes-Filho, Berna van Wendel de Joode, Yenny Alejandra Vásquez Lozada, Thereza Christina Bahia, Mónica Alejandra Quintana Cortes, Nancy Jeanet Molina Achury, Iris Andrea Moya Muñoz, and Mario Andrés Hernández Pardo. 2022. "Prenatal And Postnatal Exposure To Pesticides And School-Age Children 'S Cognitive Ability In Rural Bogotá, Colombia". Neurotoxicology 90: 112-120. doi:10.1016/j.neuro.2022.03.008.

Binter, A.C., E. Bannier, D. Saint-Amour, G. Simon, C. Barillot, C. Monfort, S. Cordier, F. Pelé, and C. Chevrier. 2020. "Exposure Of Pregnant Women To Organophosphate Insecticides And Child Motor Inhibition At The Age Of 10–12 Years Evaluated By FMRI". Environmental Research 188: 109859. doi:10.1016/j.envres.2020.109859.

Boedeker, Wolfgang, Meriel Watts, Peter Clausing, and Emily Marquez. 2020. "The Global Distribution Of Acute Unintentional Pesticide Poisoning: Estimations Based On A Systematic Review". BMC Public Health 20 (1). doi:10.1186/s12889-020-09939-0.

Bouchard, Maryse F., Jonathan Chevrier, Kim G. Harley, Katherine Kogut, Michelle Vedar, Norma Calderon, and Celina Trujillo et al. 2011. "Prenatal Exposure To Organophosphate Pesticides And IQ In 7-Year-Old Children". Environmental Health Perspectives 119 (8): 1189-1195. doi:10.1289/ehp.1003185.

Braquenier, Jean Baptiste and J C Plumier. 2007. “Gender-specific developmental neurotoxicity of cholinesterase inhibitor Phosalone in mice.” (unpublished?)

Causey, Kate, Katrin Burkart, Gwen Collman, Howard Hu, Michael Brauer, and Stephanie J London. 2020. "Increasing The Impact Of Environmental Epidemiology In The Global Burden Of Disease Project". Epidemiology 32 (1): 1-5. doi:10.1097/ede.0000000000001273.

Centres for Disease Control and Prevention, 2017, “Organophosphorus Insecticides: Dialkyl Phosphate Metabolites Factsheet” Available: https://www.cdc.gov/biomonitoring/OP-DPM_FactSheet.html

Centre for Pesticide Suicide Prevention, 2022, “Country work”. Accessed here: https://centrepsp.org/country-work/#

Centre for Pesticide Suicide Prevention, 2022, “The solution”. Accessed here:

https://centrepsp.org/the-solution2

​​Chilipweli PM, Ngowi AV, Manji K. 2021. “Maternal pesticide exposure and child neuro-development among smallholder tomato farmers in the southern corridor of Tanzania.” BMC Public Health.

Coleman, Bailey, Asad, Iqra, Heng, Yi Yan, Menard, Lauren, Benki-Nugent, Sarah, Were, Faridah Hussein, Carr, Catherine, and Megan McHenry. 2022. “Pesticides and neurodevelopment of children in low and middle-income countries: a systematic review” (pre-publication draft manuscript - for access contact Benjamin Stewart to ascertain author permission).

Costa, Lucio G. 2017. "Organophosphorus Compounds At 80: Some Old And New Issues". Toxicological Sciences 162 (1): 24-35. doi:10.1093/toxsci/kfx266.

DeSesso, John M., Rebecca E. Watson, Carl L. Keen, Keith P. Hazelden, Laurie C. Haws, and Abby A. Li. 2008. "Analysis And Integration Of Developmental Neurotoxicity And Ancillary Data Into Risk Assessment: A Case Study Of Dimethoate". Journal Of Toxicology And Environmental Health, Part A 72 (2): 94-109. doi:10.1080/15287390802477452.

Deziel, Nicole C., Melissa C. Friesen, Jane A. Hoppin, Cynthia J. Hines, Kent Thomas, and Laura E. Beane Freeman. 2015. "A Review Of Nonoccupational Pathways For Pesticide Exposure In Women Living In Agricultural Areas". Environmental Health Perspectives 123 (6): 515-524. doi:10.1289/ehp.1408273.

Donald, Carey E., Richard P. Scott, Kathy L. Blaustein, Mary L. Halbleib, Makhfousse Sarr, Paul C. Jepson, and Kim A. Anderson. 2016. "Silicone Wristbands Detect Individuals' Pesticide Exposures In West Africa". Royal Society Open Science 3 (8): 160433. doi:10.1098/rsos.160433.

Ecobichon DJ. 2001. “Pesticide use in developing countries.” Toxicology. 160(1):27–33

Ein-Mor, Eliana, Zivanit Ergaz-Shaltiel, Tamar Berman, Thomas Göen, Juma Natsheh, Avraham Ben-Chetrit, Ronit Haimov-Kochman, and Ronit Calderon-Margalit. 2018. "Decreasing Urinary Organophosphate Pesticide Metabolites Among Pregnant Women And Their Offspring In Jerusalem: Impact Of Regulatory Restrictions On Agricultural Organophosphate Pesticides Use?". International Journal Of Hygiene And Environmental Health 221 (5): 775-781. doi:10.1016/j.ijheh.2018.03.013.

Engel, Stephanie M., James Wetmur, Jia Chen, Chenbo Zhu, Dana Boyd Barr, Richard L. Canfield, and Mary S. Wolff. 2011. "Prenatal Exposure To Organophosphates, Paraoxonase 1, And Cognitive Development In Childhood". Environmental Health Perspectives 119 (8): 1182-1188. doi:10.1289/ehp.1003183.

European Chemicals Agency (ECHA), 2021. “Budget 2021”. Accessed here: https://echa.europa.eu/documents/10162/8633921/FINAL_MB_59_2020_%282%29_Budget_2021_MB60-89ugl2u2.pdf/efb223e5-c459-f6e9-7a51-aef1c1c0583c

European Chemicals Agency (ECHA), 2022. “Risk Profile on Chlorpyrifos”. Accessed here: https://echa.europa.eu/documents/10162/8a51d7d9-e9a4-2513-e975-492fb70f825c

FAO-STAT data, 2022. Accessed here: https://www.fao.org/faostat/

Fiedler, Nancy, Juthasiri Rohitrattana, Wattasit Siriwong, Panrapee Suttiwan, Pam Ohman Strickland, P. Barry Ryan, Diane S. Rohlman, Parinya Panuwet, Dana Boyd Barr, and Mark G. Robson. 2015. "Neurobehavioral Effects Of Exposure To Organophosphates And Pyrethroid Pesticides Among Thai Children". Neurotoxicology 48: 90-99. doi:10.1016/j.neuro.2015.02.003.

Fuhrimann, Samuel, Chenjie Wan, Elodie Blouzard, Adriana Veludo, Zelda Holtman, Shala Chetty-Mhlanga, and Mohamed Aqiel Dalvie et al. 2021. "Pesticide Research On Environmental And Human Exposure And Risks In Sub-Saharan Africa: A Systematic Literature Review". International Journal Of Environmental Research And Public Health 19 (1): 259. doi:10.3390/ijerph19010259.

Fuller et al. 2022. “Pollution and health: a progress update”. The Lancet Planetary Health. Vol. 6 Issue 6, E535-547.

Gaylord, Abigail, Gwendolyn Osborne, Akhgar Ghassabian, Julia Malits, Teresa Attina, and Leonardo Trasande. 2020. "Trends In Neurodevelopmental Disability Burden Due To Early Life Chemical Exposure In The USA From 2001 To 2016: A Population-Based Disease Burden And Cost Analysis". Molecular And Cellular Endocrinology 502: 110666. doi:10.1016/j.mce.2019.110666.

Gillezeau, Alpert, Joshi, and Taioli. 2019. "Urinary Dialkylphosphate Metabolite Levels In US Adults—National Health And Nutrition Examination Survey 1999–2008". International Journal Of Environmental Research And Public Health 16 (23): 4605. doi:10.3390/ijerph16234605.

GiveWell, 2021. “Centre for Pesticide Suicide Prevention — General Support (January 2021)”. Accessed here: https://www.givewell.org/research/incubation-grants/CPSP-general-support-jan-2021

Global Environment Facility, 2022. ‘Mercury’. Accessed here: https://www.thegef.org/what-we-do/topics/mercury

González-Alzaga, B., M. Lacasaña, C. Aguilar-Garduño, M. Rodríguez-Barranco, F. Ballester, M. Rebagliato, and A.F. Hernández. 2014. "A Systematic Review Of Neurodevelopmental Effects Of Prenatal And Postnatal Organophosphate Pesticide Exposure". Toxicology Letters 230 (2): 104-121. doi:10.1016/j.toxlet.2013.11.019.

GOV.PH, 2022. “FPA proposes Php 346.7M budget during DA’s internal budget session”. Accessed here: https://fpa.da.gov.ph/NW/index.php/information-resources/publications/articles/305-fpa-proposes-php-346-7m-budget-during-da-s-internal-budget-session

​​Grandjean, Philippe, and Martine Bellanger. 2017. "Calculation Of The Disease Burden Associated With Environmental Chemical Exposures: Application Of Toxicological Information In Health Economic Estimation". Environmental Health 16 (1). doi:10.1186/s12940-017-0340-3.

Grandjean, Philippe, and Philip J Landrigan. 2014. "Neurobehavioural Effects Of Developmental Toxicity". The Lancet Neurology 13 (3): 330-338. doi:10.1016/s1474-4422(13)70278-3.

Gunnell, D, R Fernando, M Hewagama, W D D Priyangika, F Konradsen, and M Eddleston. 2007. "The Impact Of Pesticide Regulations On Suicide In Sri Lanka". International Journal Of Epidemiology 36 (6): 1235-1242. doi:10.1093/ije/dym164.

​​Guo, Jianqiu, Jiming Zhang, Chunhua Wu, Shenliang Lv, Dasheng Lu, Xiaojuan Qi, and Shuai Jiang et al. 2019. "Associations Of Prenatal And Childhood Chlorpyrifos Exposure With Neurodevelopment Of 3-Year-Old Children". Environmental Pollution 251: 538-546. doi:10.1016/j.envpol.2019.05.040.

Guodong, Ding, Wang Pei, Tian Ying, Zhang Jun, Gao Yu, Wang Xiaojin, Shi Rong, Wang Guoquan, and Shen Xiaoming. 2012. "Organophosphate Pesticide Exposure And Neurodevelopment In Young Shanghai Children". Environmental Science & Technology 46 (5): 2911-2917. doi:10.1021/es202583d.

Handal AJ, Lozoff B, Breilh J, Harlow SD. 2007. “Neurobehavioral Development in Children With Potential Exposure to Pesticides.” Epidemiology. 18(3):312–20.

Handal AJ, Harlow SD, Breilh J, Lozoff B. 2008. “Occupational Exposure to Pesticides During Pregnancy and Neurobehavioral Development of Infants and Toddlers.” Epidemiology. 19(6):851–9

Handford CE, Elliott CT, Campbell K. 2015. “A review of the global pesticide legislation and the scale of challenge in reaching the global harmonization of food safety standards.” Integr Environ Assess Manag. 11(4):525–36;

Henck & Morford, 2010. “Developmental Toxicology” in Comprehensive Toxicology. Accessed here: https://www.sciencedirect.com/topics/neuroscience/developmental-neurotoxicology

Hernandez‐Castro, Ixel, Sandrah P. Eckel, Thomas Chavez, Mark Johnson, Deborah Lerner, Brendan Grubbs, and Claudia M. Toledo‐Corral et al. 2021. "Household Pesticide Exposures And Infant Gross Motor Development In The MADRES Cohort". Paediatric And Perinatal Epidemiology 36 (2): 220-229. doi:10.1111/ppe.12850.

Hertz-Picciotto, Irva, Jennifer B. Sass, Stephanie Engel, Deborah H. Bennett, Asa Bradman, Brenda Eskenazi, Bruce Lanphear, and Robin Whyatt. 2018. "Organophosphate Exposures During Pregnancy And Child Neurodevelopment: Recommendations For Essential Policy Reforms". PLOS Medicine 15 (10): e1002671. doi:10.1371/journal.pmed.1002671.

Hioki, Keisuke, Yuki Ito, Naoko Oya, Shoji F. Nakayama, Tomohiko Isobe, Takeshi Ebara, and Kanemitsu Shibata et al. 2019. "Intra-Individual Variations Of Organophosphate Pesticide Metabolite Concentrations In Repeatedly Collected Urine Samples From Pregnant Women In Japan". Environmental Health And Preventive Medicine 24 (1). doi:10.1186/s12199-019-0761-4.

Ibrahim, Khairy A., Mohammed Eleyan, Heba Ali Abd El-Rahman, Soad A. Khwanes, and Rania A. Mohamed. 2020. "Quercetin Attenuates The Oxidative Injury–Mediated Upregulation Of Apoptotic Gene Expression And Catecholaminergic Neurotransmitters Of The Fetal Rats’ Brain Following Prenatal Exposure To Fenitrothion Insecticide". Neurotoxicity Research 37 (4): 871-882. doi:10.1007/s12640-020-00172-6.

International Pollutants Elimination Network, 2022. “Mercury”. Accessed here: https://ipen.org/tags/mercury

​​Jaacks, Lindsay M., Nancy Diao, Antonia M. Calafat, Maria Ospina, Maitreyi Mazumdar, Md Omar Sharif Ibne Hasan, Robert Wright, Quazi Quamruzzaman, and David C. Christiani. 2019. "Association Of Prenatal Pesticide Exposures With Adverse Pregnancy Outcomes And Stunting In Rural Bangladesh". Environment International 133: 105243. doi:10.1016/j.envint.2019.105243.

Jusko, Todd A., Michiel A. van den Dries, Anjoeka Pronk, Pamela A. Shaw, Mònica Guxens, Suzanne Spaan, Vincent W. Jaddoe, Henning Tiemeier, and Matthew P. Longnecker. 2019. "Organophosphate Pesticide Metabolite Concentrations In Urine During Pregnancy And Offspring Nonverbal IQ At Age 6 Years". Environmental Health Perspectives 127 (1): 017007. doi:10.1289/ehp3024.

Kongtip, Pornpimol, Noppanun Nankongnab, Susan Woskie, Akkarat Phamonphon, Prapin Tharnpoophasiam, Kitsiluck Wilaiwan, and Punnee Srasom. 2013. "Organophosphate Urinary Metabolite Levels During Pregnancy, Delivery And Postpartum In Women Living In Agricultural Areas In Thailand". Journal Of Occupational Health 55 (5): 367-375. doi:10.1539/joh.13-0040-oa.

Koureas, Michalis, Andreas Tsakalof, Aristidis Tsatsakis, and Christos Hadjichristodoulou. 2012. "Systematic Review Of Biomonitoring Studies To Determine The Association Between Exposure To Organophosphorus And Pyrethroid Insecticides And Human Health Outcomes". Toxicology Letters 210 (2): 155-168. doi:10.1016/j.toxlet.2011.10.007.

Krewski, D., M. E. Andersen, M. G. Tyshenko, K. Krishnan, T. Hartung, K. Boekelheide, and J. F. Wambaugh et al. 2019. "Toxicity Testing In The 21St Century: Progress In The Past Decade And Future Perspectives". Archives Of Toxicology 94 (1): 1-58. doi:10.1007/s00204-019-02613-4.

Lee, Y Y, D Chisholm, M Eddleston, D Gunnell, A Fleischmann, F Konradsen, and M Y Bertram et al. 2021. "The Cost-Effectiveness Of Banning Highly Hazardous Pesticides To Prevent Suicides Due To Pesticide Self-Ingestion Across 14 Countries: An Economic Modelling Study". The Lancet Global Health 9 (3): e291-e300. doi:10.1016/s2214-109x(20)30493-9.

Li, Adela Jing, and Kurunthachalam Kannan. 2018. "Urinary Concentrations And Profiles Of Organophosphate And Pyrethroid Pesticide Metabolites And Phenoxyacid Herbicides In Populations In Eight Countries". Environment International 121: 1148-1154. doi:10.1016/j.envint.2018.10.033.

Li, Mengmeng, Rui Wang, Chang Su, Jianwen Li, and Zhenyu Wu. 2022. "Temporal Trends Of Exposure To Organochlorine Pesticides In The United States: A Population Study From 2005 To 2016". International Journal Of Environmental Research And Public Health 19 (7): 3862. doi:10.3390/ijerph19073862.

Li, Yan, Xianyu Wang, Jean Feary McKenzie, Andrea 't Mannetje, Soo Cheng, Chang He, and Janet Leathem et al. 2022. "Pesticide Exposure In New Zealand School-Aged Children: Urinary Concentrations Of Biomarkers And Assessment Of Determinants". Environment International 163: 107206. doi:10.1016/j.envint.2022.107206.

​​Liu, Hanhua, Chalalai Hanchenlaksh, Andrew C. Povey, and Frank de Vocht. 2014. "Pesticide Residue Transfer In Thai Farmer Families: Using Structural Equation Modeling To Determine Exposure Pathways". Environmental Science & Technology 49 (1): 562-569. doi:10.1021/es503875t.

Liu, XingYu, QiuPing Zhang, ShiBao Li, Ping Mi, DongYan Chen, Xin Zhao, and XiZeng Feng. 2018. "Developmental Toxicity And Neurotoxicity Of Synthetic Organic Insecticides In Zebrafish (Danio Rerio): A Comparative Study Of Deltamethrin, Acephate, And Thiamethoxam". Chemosphere 199: 16-25. doi:10.1016/j.chemosphere.2018.01.176.

Lu, Chensheng, Christa Essig, Christa Root, Diane S Rohlman, Tom McDonald, and Stephen Sulzbacher. 2009. "Assessing The Association Between Pesticide Exposure And Cognitive Development In Rural Costa Rican Children Living In Organic And Conventional Coffee Farms". International Journal Of Adolescent Medicine And Health 21 (4). doi:10.1515/ijamh.2009.21.4.609.

​​Malits, Julia, Mrudula Naidu, and Leonardo Trasande. 2022. "Exposure To Endocrine Disrupting Chemicals In Canada: Population-Based Estimates Of Disease Burden And Economic Costs". Toxics 10 (3): 146. doi:10.3390/toxics10030146.

Martins Laurentino, Ana Olívia, Fabiana Durante de Medeiros, Juliana de Oliveira, Naiana da Rosa, Tamires Mateus Gomes, Eduardo de Medeiros Peretti, Josiane Somariva Prophiro, and Jucélia J. Fortunato. 2019. "Effects Of Prenatal Exposure To Temephos On Behavior And Social Interaction". Neuropsychiatric Disease And Treatment Volume 15: 669-673. doi:10.2147/ndt.s193896.

Mastorci, Francesca, Nunzia Linzalone, Lamia Ait-Ali, and Alessandro Pingitore. 2021. "Environment In Children’S Health: A New Challenge For Risk Assessment". International Journal Of Environmental Research And Public Health 18 (19): 10445. doi:10.3390/ijerph181910445.

Morgan, Marsha K, Linda S Sheldon, Paul A Jones, Carry W Croghan, Jane C Chuang, and Nancy K Wilson. 2010. "The Reliability Of Using Urinary Biomarkers To Estimate Children's Exposures To Chlorpyrifos And Diazinon". Journal Of Exposure Science &Amp; Environmental Epidemiology 21 (3): 280-290. doi:10.1038/jes.2010.11.

Muñoz-Quezada, María Teresa, Boris A. Lucero, Dana B. Barr, Kyle Steenland, Karen Levy, P. Barry Ryan, and Veronica Iglesias et al. 2013. "Neurodevelopmental Effects In Children Associated With Exposure To Organophosphate Pesticides: A Systematic Review". Neurotoxicology 39: 158-168. doi:10.1016/j.neuro.2013.09.003.

Naksen, Warangkana, Tippawan Prapamontol, Ampica Mangklabruks, Somporn Chantara, Prasak Thavornyutikarn, Niphan Srinual, Parinya Panuwet, P. Barry Ryan, Anne M. Riederer, and Dana Boyd Barr. 2015. "Associations Of Maternal Organophosphate Pesticide Exposure And PON1 Activity With Birth Outcomes In SAWASDEE Birth Cohort, Thailand". Environmental Research 142: 288-296. doi:10.1016/j.envres.2015.06.035.

National Research Council, 2007. “Toxicity testing in the 21st century: a vision and a strategy.” Washington, DC: National Academies Press

Nkinsa, Patrick, Gina Muckle, Pierre Ayotte, Bruce P. Lanphear, Tye E. Arbuckle, William D. Fraser, and Maryse F. Bouchard. 2020. "Organophosphate Pesticides Exposure During Fetal Development And IQ Scores In 3 And 4-Year Old Canadian Children". Environmental Research 190: 110023. doi:10.1016/j.envres.2020.110023.

Onchoi et al. 2020. “Organophosphates in meconium of newborn babies whose mothers resided in agricultural areas of Thailand”. Southeast Asian J Trop Med Public Health. 2020 Mar 2; 51(1): 77–87

Our World in Data, 2022. How the world eliminated lead from gasoline. Accessed here: https://ourworldindata.org/leaded-gasoline-phase-out

Ramírez-Santana, Muriel, Liliana Zúñiga-Venegas, Sebastián Corral, Nel Roeleveld, Hans Groenewoud, Koos van der Velden, Paul T.J. Scheepers, and Floria Pancetti. 2020. "Association Between Cholinesterase's Inhibition And Cognitive Impairment: A Basis For Prevention Policies Of Environmental Pollution By Organophosphate And Carbamate Pesticides In Chile". Environmental Research 186: 109539. doi:10.1016/j.envres.2020.109539.

Rauh, Virginia, Srikesh Arunajadai, Megan Horton, Frederica Perera, Lori Hoepner, Dana B. Barr, and Robin Whyatt. 2011. "Seven-Year Neurodevelopmental Scores And Prenatal Exposure To Chlorpyrifos, A Common Agricultural Pesticide". Environmental Health Perspectives 119 (8): 1196-1201. doi:10.1289/ehp.1003160.

Ross, Sarah Mackenzie, I. C. McManus, Virginia Harrison, and Oliver Mason. 2012. "Neurobehavioral Problems Following Low-Level Exposure To Organophosphate Pesticides: A Systematic And Meta-Analytic Review". Critical Reviews In Toxicology 43 (1): 21-44. doi:10.3109/10408444.2012.738645.

Rowe, Christopher, Robert Gunier, Asa Bradman, Kim G. Harley, Katherine Kogut, Kimberly Parra, and Brenda Eskenazi. 2016. "Residential Proximity To Organophosphate And Carbamate Pesticide Use During Pregnancy, Poverty During Childhood, And Cognitive Functioning In 10-Year-Old Children". Environmental Research 150: 128-137. doi:10.1016/j.envres.2016.05.048.

Peng, Feng-Jiao, Emilie M. Hardy, Sakina Mezzache, Nasrine Bourokba, Paul Palazzi, Natali Stojiljkovic, Philippe Bastien, Jing Li, Jeremie Soeur, and Brice M.R. Appenzeller. 2020. "Exposure To Multiclass Pesticides Among Female Adult Population In Two Chinese Cities Revealed By Hair Analysis". Environment International 138: 105633. doi:10.1016/j.envint.2020.105633.

Persson, Linn, Bethanie M. Carney Almroth, Christopher D. Collins, Sarah Cornell, Cynthia A. de Wit, Miriam L. Diamond, and Peter Fantke et al. 2022. "Outside The Safe Operating Space Of The Planetary Boundary For Novel Entities". Environmental Science & Technology 56 (3): 1510-1521. doi:10.1021/acs.est.1c04158.

Pesticide Action Network, 2018, “Of rights and poisons: Accountability of the agrochemical industry.” Accessed here: https://panap.net/resource/of-rights-and-poisons-accountability-of-the-agrochemical-industry/?ind=1594041857622&filename=Of-Rights-and-Poisons-Accountability-of-the-Agrochemical-Industry.pdf&wpdmdl=2091&refresh=62945ed8c88531653890776

Pesticide Action Network, 2022, “PAN INTERNATIONAL CONSOLIDATED LIST OF BANNED PESTICIDES”. Accessed here: https://pan-international.org/pan-international-consolidated-list-of-banned-pesticides/

Plant, Michael. 2022. “A philosophical review of Open Philanthropy’s Cause Prioritisation Framework.” EA Forum. Accessed here: https://forum.effectivealtruism.org/posts/bdiDW83SFAsoA4EeB/a-philosophical-review-of-open-philanthropy-s-cause

Pure Earth, 2022. “Global Mercury Program”. Accessed here: https://www.pureearth.org/our-projects/global-mercury-program/

Sagiv, Sharon K., Jennifer L. Bruno, Joseph M. Baker, Vanessa Palzes, Katherine Kogut, Stephen Rauch, Robert Gunier, Ana M. Mora, Allan L. Reiss, and Brenda Eskenazi. 2019. "Prenatal Exposure To Organophosphate Pesticides And Functional Neuroimaging In Adolescents Living In Proximity To Pesticide Application". Proceedings Of The National Academy Of Sciences 116 (37): 18347-18356. doi:10.1073/pnas.1903940116.

SAICM 2020. “Community of practice highly hazardous pesticides: Discussion digest”. Accessed here: https://saicmknowledge.org/sites/default/files/meterial/SAICM_UCT%20HHP%20CoP%20Digest%20of%20the%20Global%20Action%20Plan%20%20Discussion%20DIGEST%2021%2010%202020%20doc.pdf

SAICM, 2021. “Revised draft Programme of Work and Budget 2021-2023 for the

Secretariat of the Strategic Approach”. Accessed here: http://www.saicm.org/Portals/12/Documents/meetings/Bureau/ICCM5B17/SAICM_ICCM5-Bureau_TC_9_5_%20Revised%20draft%20PoW%20and%20Budget%202021-2023.pdf

SAICM, 2022. “SAICM ROADMAP TOWARDS IP4 AND ICCM5”. Accessed here: http://www.saicm.org/Portals/12/Documents/meetings/Bureau/ICCM5B20/SAICM_ICCM5-Bureau_TC_11_2_IP4%20and%20ICCM5%20Roadmap.pdf

Salama, Mohamed, Ahmed Lotfy, Khaled Fathy, Maria Makar, Mona El-emam, Aya El-gamal, Mohamed El-gamal, Ahmad Badawy, Wael M.Y. Mohamed, and Mohamed Sobh. 2015. "Developmental Neurotoxic Effects Of Malathion On 3D Neurosphere System". Applied &Amp; Translational Genomics 7: 13-18. doi:10.1016/j.atg.2015.07.001.

Sapbamrer, Ratana, and Surat Hongsibsong. 2019. "Effects Of Prenatal And Postnatal Exposure To Organophosphate Pesticides On Child Neurodevelopment In Different Age Groups: A Systematic Review". Environmental Science And Pollution Research 26 (18): 18267-18290. doi:10.1007/s11356-019-05126-w.

Scott, Natasha B., and Nicola S. Pocock. 2021. "The Health Impacts Of Hazardous Chemical Exposures Among Child Labourers In Low- And Middle-Income Countries". International Journal Of Environmental Research And Public Health 18 (10): 5496. doi:10.3390/ijerph18105496.

SDG Knowledge Hub, 2021, Accessed here: https://sdg.iisd.org/events/international-conference-on-chemicals-management-iccm5/

Sheppard, Lianne, Seth McGrew, and Richard A. Fenske. 2020. "Flawed Analysis Of An Intentional Human Dosing Study And Its Impact On Chlorpyrifos Risk Assessments". Environment International 143: 105905. doi:10.1016/j.envint.2020.105905.

Silver, Monica K., Jie Shao, Binquan Zhu, Minjian Chen, Yankai Xia, Niko Kaciroti, Betsy Lozoff, and John D. Meeker. 2017. "Prenatal Naled And Chlorpyrifos Exposure Is Associated With Deficits In Infant Motor Function In A Cohort Of Chinese Infants". Environment International 106: 248-256. doi:10.1016/j.envint.2017.05.015.

Solomon, Gina. 2021. ‘The EPA is banning chlorpyrifos, a pesticide widely used on food crops, after 14 years of pressure from environmental and labor groups’ The Conversation. Accessed here: https://theconversation.com/the-epa-is-banning-chlorpyrifos-a-pesticide-widely-used-on-food-crops-after-14-years-of-pressure-from-environmental-and-labor-groups-166485

Spaan, Suzanne, Anjoeka Pronk, Holger M Koch, Todd A Jusko, Vincent W V Jaddoe, Pamela A Shaw, Henning M Tiemeier, Albert Hofman, Frank H Pierik, and Matthew P Longnecker. 2014. "Reliability Of Concentrations Of Organophosphate Pesticide Metabolites In Serial Urine Specimens From Pregnancy In The Generation R Study". Journal Of Exposure Science &Amp; Environmental Epidemiology 25 (3): 286-294. doi:10.1038/jes.2014.81.

Stockholm Convention, 2022. “Chemicals proposed for listing under the Convention” Accessed here: http://chm.pops.int/TheConvention/ThePOPs/ChemicalsProposedforListing/tabid/2510/Default.aspx

Sudakin, Daniel L., and David L. Stone. 2011. "Dialkyl Phosphates As Biomarkers Of Organophosphates: The Current Divide Between Epidemiology And Clinical Toxicology". Clinical Toxicology 49 (9): 771-781. doi:10.3109/15563650.2011.624101.

​​Suwannakul, Boonsita, Ratana Sapbamrer, Natrujee Wiwattanadittakul, and Surat Hongsibsong. 2021. "Organophosphate Pesticide Exposures In Early And Late Pregnancy Influence Different Aspects Of Infant Developmental Performance". Toxics 9 (5): 99. doi:10.3390/toxics9050099.

Tarazona, Jose V., Maria del Carmen González-Caballero, Mercedes de Alba-Gonzalez, Susana Pedraza-Diaz, Ana Cañas, Noelia Dominguez-Morueco, and Marta Esteban-López et al. 2022. "Improving The Risk Assessment Of Pesticides Through The Integration Of Human Biomonitoring And Food Monitoring Data: A Case Study For Chlorpyrifos". Toxics 10 (6): 313. doi:10.3390/toxics10060313.

Thistle, Jake E., Amanda Ramos, Kyle R. Roell, Giehae Choi, Cherrel K. Manley, Amber M. Hall, and Gro D. Villanger et al. 2022. "Prenatal Organophosphorus Pesticide Exposure And Executive Function In Preschool-Aged Children In The Norwegian Mother, Father And Child Cohort Study (Moba)". Environmental Research 212: 113555. doi:10.1016/j.envres.2022.113555.

Todd, Spencer W., Eric W. Lumsden, Yasco Aracava, Jacek Mamczarz, Edson X. Albuquerque, and Edna F.R. Pereira. 2020. "Gestational Exposures To Organophosphorus Insecticides: From Acute Poisoning To Developmental Neurotoxicity". Neuropharmacology 180: 108271. doi:10.1016/j.neuropharm.2020.108271.

ToxicsLink, 2019. “2018-2019 Annual Report”. Accessed here: http://toxicslink.org/docs/Toxics%20Link%20-%20Annual%20Report%202018-19%20final.pdf

UN Environment Programme, 2019. “Global chemicals outlook II: from legacies to innovative solutions: implementing the 2030 Agenda for Sustainable Development.” Geneva: United Nations Environment Programme. Accessed here: https://www.unenvironment.org/explore-topics/chemicals-waste/what-we-do/policy-and-governance/globalchemicals-outlook

United Nations Environment Program, 2020. “2020 Update on the Global Status of Legal Limits on Lead in Paint”. Accessed here: https://www.unep.org/resources/report/2020-update-global-status-legal-limits-lead-paint

United Nations, 2022. “Synthesis Report on the Environmental and Health Impacts of Pesticides and Fertilizers and Ways to Minimize Them: Envisioning a Chemical-safe World” Accessed here: https://wedocs.unep.org/handle/20.500.11822/38409

van den Dries, Michiel A., Sander Lamballais, Hanan El Marroun, Anjoeka Pronk, Suzanne Spaan, Kelly K. Ferguson, Matthew P. Longnecker, Henning Tiemeier, and Mònica Guxens. 2020. "Prenatal Exposure To Organophosphate Pesticides And Brain Morphology And White Matter Microstructure In Preadolescents". Environmental Research 191: 110047. doi:10.1016/j.envres.2020.110047.

van den Dries, Michiel A., Kelly K. Ferguson, Alexander P. Keil, Anjoeka Pronk, Suzanne Spaan, Akhgar Ghassabian, and Susana Santos et al. 2021. "Prenatal Exposure To Nonpersistent Chemical Mixtures And Offspring IQ And Emotional And Behavioral Problems". Environmental Science & Technology 55 (24): 16502-16514. doi:10.1021/acs.est.1c04455.

Vasamsetti, Krishna, Bala Murali, Nam Seok Kim, Kyongmi Chon, and Hong-Hyun Park. 2020. "Developmental Toxic Effects Of Phosmet On Zebrafish (Danio Rerio) Embryos". The Korean Journal Of Pesticide Science 24 (4): 343-351. doi:10.7585/kjps.2020.24.4.343.

Voorhees, Jaymie R., Diane S. Rohlman, Pamela J. Lein, and Andrew A. Pieper. 2017. "Neurotoxicity In Preclinical Models Of Occupational Exposure To Organophosphorus Compounds". Frontiers In Neuroscience 10. doi:10.3389/fnins.2016.00590.

​​Weerasinghe, Manjula, Melissa Pearson, Flemming Konradsen, Suneth Agampodi, J. A. Sumith, Shaluka Jayamanne, S. M. H. M. K. Senanayake, Sandamali Rajapaksha, and Michael Eddleston. 2020. "Emerging Pesticides Responsible For Suicide In Rural Sri Lanka Following The 2008–2014 Pesticide Bans". BMC Public Health 20 (1). doi:10.1186/s12889-020-08871-7.

White R. F., et al. 2011. “Functional MRI approach to developmental methylmercury and polychlorinated biphenyl neurotoxicity.” Neurotoxicology 32, 975–980

Wikipedia - “Fertilizer and Pesticide Authority”, Accessed here: https://en.wikipedia.org/wiki/Fertilizer_and_Pesticide_Authority

Wikipedia, “Organophosphates: Pesticides”, Accessed here: https://en.wikipedia.org/wiki/Organophosphate#Pesticides

Wikipedia - “Pesticides Action Network”, Accessed here: https://en.wikipedia.org/wiki/Pesticide_Action_Network

Wikipedia - “Registration, Evaluation, Authorisation and Restriction of Chemicals”, Accessed here: https://en.wikipedia.org/wiki/Registration,_Evaluation,_Authorisation_and_Restriction_of_Chemicals

Williams, Megan K., Andrew Rundle, Darrell Holmes, Marilyn Reyes, Lori A. Hoepner, Dana B. Barr, David E. Camann, Frederica P. Perera, and Robin M. Whyatt. 2008. "Changes In Pest Infestation Levels, Self-Reported Pesticide Use, And Permethrin Exposure During Pregnancy After The 2000–2001 U.S. Environmental Protection Agency Restriction Of Organophosphates". Environmental Health Perspectives 116 (12): 1681-1688. doi:10.1289/ehp.11367.

​​Wilson, Nancy K, Warren J Strauss, Nicole Iroz-Elardo, and Jane C Chuang. 2009. "Exposures Of Preschool Children To Chlorpyrifos, Diazinon, Pentachlorophenol, And 2,4-Dichlorophenoxyacetic Acid Over 3 Years From 2003 To 2005: A Longitudinal Model". Journal Of Exposure Science &Amp; Environmental Epidemiology 20 (6): 546-558. doi:10.1038/jes.2009.45.

World Bank, 2016. ‘Agribusiness rules lag in agriculture dependent countries’. Accessed here: https://www.worldbank.org/en/news/press-release/2016/01/28/agribusiness-rules-lag-in-agriculture-dependent-countries

​​World Bank, 2022. Accessed here: https://data.worldbank.org/country/XO

Xie, Xinyan, Yanjian Wan, Bing Zhu, Qi Liu, Kaiheng Zhu, Qi Jiang, and Yanan Feng et al. 2022. "Association Between Urinary Dialkylphosphate Metabolites And Dyslexia Among Children From Three Cities Of China: The READ Program". Science Of The Total Environment 814: 151852. doi:10.1016/j.scitotenv.2021.151852.

Xu, Mengmeng, and Fangxing Yang. 2020. "Integrated Gender-Related Effects Of Profenofos And Paclobutrazol On Neurotransmitters In Mouse". Ecotoxicology And Environmental Safety 190: 110085. doi:10.1016/j.ecoenv.2019.110085.

Yuan W., et al. 2006. “The impact of early childhood lead exposure on brain organization: A functional magnetic resonance imaging study of language function.” Pediatrics 118, 971–977

Zare Jeddi, Maryam, Nancy B. Hopf, Susana Viegas, Anna Bal Price, Alicia Paini, Christoph van Thriel, and Emilio Benfenati et al. 2021. "Towards A Systematic Use Of Effect Biomarkers In Population And Occupational Biomonitoring". Environment International 146: 106257. doi:10.1016/j.envint.2020.106257.

Zhang, Yanxu, Zhengcheng Song, Shaojian Huang, Peng Zhang, Yiming Peng, Peipei Wu, and Jing Gu et al. 2021. "Global Health Effects Of Future Atmospheric Mercury Emissions". Nature Communications 12 (1). doi:10.1038/s41467-021-23391-7.

Zidenberg-Cherr S, Neyman M, Fechner K, Sutherlin J, Johns M, Lamp C, et al. 2000. “Nutrition may influence toxicant susceptibility of children and elderly.” Calif Agric. 54(5):19–25.