Toxicology+and+POP's

// Question:Hypothetically if a A new chemical compound has been synthesized to be used as an insecticide. What is the best formula/schedule to predict its possible toxic effects in man and environment, and furthermore to prevent health risks in population level? By Paula Williams 2010 for School of Arctic Medicine at University of Oulu, Finland Masters Circumpolar H.ealth. //

INTRODUCTION: We live in a vicious circle when it comes down to nature. As we know agriculture brings with it pesticides and other chemicals and, should pests thrive in a warming North then farmers may have no choice but to resort to increased reliance on pesticides to protect crops.The question though lies in the balance of nature for cause and effect. Rather, what impact does this have on the environment for health and wellbeing? The ‘catch 22’ problem lies today in insecticides producing as little toxic effect on human life as well as the local environment and its capability not to travel across distances and be biodegradable. Is there such an insecticide ?

There are several models and formulas that toxicologists use to analyse new chemicals especially the dioxins found in many insecticides such as tetrachlorodibenzo-p-dioxin (TCDD)which is one of the most toxic synthetic compounds that has varying degrees of sensitivity amongst species. With a lethal dose (LD50) [1] these anthropogenic chemicals have harmful toxicity effect on biota.In the last 20 years levels of chlorinated dibenzo-p-dioxins (CDDs) like TCDD found in the soil have been a concern to scientists for harmful effects from exposure to human populations from ingestion of contaminated food and water.For example health risk analysis on TCDD toxic equivalents (TEQs) have been detected in varying degrees infish, beef, dairy and vegetablesand are known to be associated with increase risk of cancers especially for soft tissue sarcomas,lung cancer and neoplasms. Furthermore, studies have found TCDD exposure to human populations have been related to cause hepatic disease, diabetes, and endocrine disorders .and in particular altered reproductive hormone levels.

If for instance, there is a new chemical compound synthesized to be used as an insecticide one of the best schedules to predict its possible toxic effects in man and environment is following the criteria for identification of ‘new’ POPs under the Stockholm Convention (2001) which identifies the chemical structure including specification of isomers where applicable. The identity and the structure of the new chemical compound’s class would be cross examined over four key areas to identify it’s: 1. ** Bioaccumulation Persistence ** The half-life of the chemical in water is greater than two months, or the half- life in soil is greater than six months, or the half-life in sediment is greater than six months. Other evidence that the chemical is sufficiently persistent to justify its consideration

2. ** Potential for long-range ** Evidence that the bio-concentration factor or bioaccumulation factor in aquatic species is greater than 5000. The logarithm of the octanol-water partition coefficient (log Kow) is greater than??? Evidence that a chemical presents other reasons for concern, such as high bioaccumulation in other species, high toxicity or ecotoxicity. Monitoring data in biota indicating that the bioaccumulation potential of the chemical is sufficient to justify its consideration.

3. ** Environmental transport ** Measured levels of the chemical in locations distant from the sources of its release that are of potential concern. Monitoring data showing that long-range environmental transport of the chemical, with the potential for transfer to a receiving environment, may have occurred via air, water, or migratory species. Environmental fate properties and/or model results that demonstrate that the chemical has a potential for long-range environmental transport through air, water or migratory species.

4. ** Adverse effects ** The half-life in air is greater than two days. Evidence of adverse effects to human health or to the environment that justifies consideration. Toxicity or eco-toxicity data that indicate the potential for damage to human health or to the environment.

Many communities today have growing fears of trans-boundary air pollution across the Arctic from long range CDD by-products by other territories industrial operations which are causing great concerns. The inhalation exposure of CDD’s have harmful effects to human populations especially those local populations that are unaware of these activities and have no precautionary understanding and protection strategies in particular the indigenous communities. Hence, t he Environmental Doctrine and the Fundamentals of the State Policy in Chemical Safety, recommend that a source inventory system be developed and implemented in the Arctic administrative territories inhabited by the indigenous peoples. Some member countries of the Arctic Council have ratified the Stockholm Convention on Persistent Organic Pollutants (POP), and joined the Aarhus Persistent Organic Pollutants and Heavy Metals Protocols of the UN-ECE convention on long range.The Arctic council members have also taken active measures in the international arena to ensure the reduction, and in the future, the full elimination of environmental and human health threats from global PTS.

Using pharmokinetic modeling the World Health Organisation (WHO)established a tolerable daily intake (TDI) of 10pg/kg/day for TCDD.However, the Food and Drug Administration including the Committee to Coordinate Environmental Health and Related Programs introduced a much lower risk-specific dose of 0.6 pg/kg/day almost half of the TDI estimated by WHO.Hence, the Environmental Protection Agency (EPA) regularly review and update any health effects from chemical toxins in particular from dioxin exposure. In addition, to assist with the chemical specific toxicological data for scientific communities the Agency for Toxic Substances and Disease Registry (ATSDR) develops toxicological profiles which provide risk associated exposure and minimal risk levels (MRL’s) to contaminants of hazardous chemicals such as dioxins found in pesticides /insecticides. If we consider our example of the new chemical compound synthesized for the purpose of being used as an insecticide then ATSDR would calculate the MRL specific value to this new compound by a formula that estimates exposure level to this compound at which adverse health effects are not expected to occur from inhalation or ingestion to human population.

The minimal risk level is calculated from the most sensitive end point for the exposure time which ranges from the highest non observed adverse effect level (NOAEL) to the lowest observed adverse effect level (LOAEL) in mg/kg/day respectively by the uncertainty factor (UF) times the modifying factor (MF). This is usually experiemented on mice, rats and rabbits. The formula for derivation of an ingested exposure to our new chemical compound would calculate the MRL through experimental studies in animals to identify the MRL as: MRL=__NOAEL (LOAEL)__ (UF x MF__)__

Animal experimentation provide valuable informative data collection in relation to toxic compounds such as dioxins like CDD’s and their toxicity effects on biota in a particular region and predict human populations exposure in general. Therefore, by multiplying the MRL by the body weight and dividing this by the ingestion rate one can calculate the contaminant level for hazardous waste sites for air, water and soil to provide comparative data evaluation guides for the environment (EMEGs) and health guides.

Food and waterunfortunately are the major source of TCDD exposure in human populations because of the fact that insecticide contaminated soil will adversely affect biota and consequently enter the food chain.Because the manner in which contaminants enter and concentrate in these two food webs is so different, the balance between terrestrial and aquatic food items in the food chain will be a pivotal point of change in exposure to biomagnifying contaminants. It is no wonder that there are numerous models and formulas to calculate, predict and analyse possible toxic effects in man and environment and provide safe guidelines to prevent health risks in population levels. The AMAP [2] state that information about nutrient and food intakes should be combined with assessments of dietary exposure to contaminants and contaminant levels in foods Interestingly, in Greenland and Canada. The findings indicated that large proportions of the studied populations in Greenland exceeded the TDI values set for chlordanes and Hg. Studies in other Arctic regions, undertaken on single food items from game, revealed relatively high levels of contaminants in marine mammals, especially polar bears and some seabird species. Organic contaminant levels in marine mammals are highest in the blubber, while Hg was found in highest concentrations in liver and kidney.The investigated contaminant levels in local marine food sources appear to be decreasing for PCBs and DDT in Arctic Canada and Russia and for PCBs in Greenland,unlike mercury levels which seems to be increased according to AMAP report. If climate warming within Arctic drainage basins continues as seen in the southern portion of the Mackenzie Basin in North America this then potentially could expand the area for cultivation and agriculture. Rather, under a global warming scenario this region is projected to contribute an additional 10 million hectares of land suitable for small grain crops [3] an area that might be further expanded with the development of new ‘climate’ resistant crops. This then increases insects and other pests to flourish in these warmer cultivated locations and so in turn require pesticides (toxaphene, DDT, hexachlorohexane and other insecticides) to control the crops from being devastated, let alone harbour reservoirs to host vector borne disease. This is a vicious circle. Any criteria proposed for the limitation of POPs in human blood and tissues necessarily involve a large number of uncertainties, due to the lack of precise toxicological data.

To make relevant predictions there must be information available on:
 * the substance and its chemical and physical properties
 * the biological system affected
 * the effects or response caused by the substance
 * the exposure (dose, time, situation)

This information is obtained from laboratory tests with cells, bacteria, animals and from accidents involving the substance. Large amounts of toxicological information are collected into data bases and data banks. This includes identification of data needs such as physical and chemical properties. Some of the physical and chemical properties are determined through Henry’s law constant (Kow, Koc, vapor pressure,) which can sufficiently characterizer most of PAHs and allow prediction of their environmental fate. This is because PAHs have low water solubilities. The Henry’s law constant is the partition coefficient that expresses the ratio of the chemical’s concentrations in air and water at equilibrium and is used as an indicator of a chemical’s potential to volatilize. [4] Other data prediction on new chemical compounds is the exposure and quantity (LC 50) the routes for which they may enter the body eg transplacental, bloodstream, inhalation, ingestion. All this data can be used by organizations like WHO which also derive formulas and schedules for monitoring risk assessment for pesticides especially for drinking water.

European Union (EU) standards have generally followed the World Health Organization (WHO) guidelines. The current EU drinking water directive covers 62 parameters. In the new proposal, control of 35 of these parameters is still required and 13 new parameters have been added. This gives 48 parameters in total. Because our toxicological understanding has advanced there has been some changes in European legislation, for example in the case of fluoranthene. Based on recent toxicological data, fluoranthene has been removed from the suite of PAHs used as the basis for the standard for PAHs in old coal tar linings of water mains. This standard was not based on health, and the presence of fluoranthene, which is one of the most water soluble PAHs, caused numerous breaches of the standard in otherwise excellent waters. Informed risk assessment demonstrated that the levels encountered were not of concern. In the case of potentially carcinogenic pesticides, a distinction was made according to their genotoxic potential. With non-genotoxic carcinogens, a threshold dose was assumed, and guidelines were derived using the TDI approach. WHO has derived drinking water guidelines formula for some 40 pesticides [5] This means that in cases where insecticides like our new chemical compound exhibiting threshold effects, a tolerable daily intake (TDI) is derived in the traditional manner as mentioned before when describing EMEG’s guides by dividing the no-observed-adverse-effect level (NOAEL) or the lowest-observed-adverse-effect level (LOAEL) for the critical effect by an uncertainty factor accounting for interspecies and intraspecies variation, as well as, whenever necessary, the adequacy of studies or database and the nature and severity of effects. Therefore for our new chemical insecticide it would be evaluated against the following guideline [6] value which was derived from the TDI by multiplication with body weight (bw; 60 kg for adults, 10 kg for children, 5 kg for infants) and the proportion of total intake accounted for by drinking water (P; 10% by default if no data exist), and divided by the daily drinking water consumption (C: 2 litres for adults, 1 litre for children, 0.75 litre for infants):

This prediction formula will assist toupdate new data on new chemical compounds synthesised for the use of insecticides for potential risk assessment with potentially high exposure from food. While the use of organochlorine pesticides has declined in industrialized countries, their use continues in developing countries for public health as well as for agricultural purposes. Importantly, organochlorine compounds are renowned to be persistent in the environment especially in drinking water. The toxicological basis of these guideline values and exposure assumptions made, as reflected in the percentage allocation of the TDI to drinking water, can be cross referenced for potential risk assessment and is pivotal marker for any new insecticide compound that is being produced. Furthermore, if our new chemical compound was to be used as an insecticide anywhere in Europe it would today need to satisfy the regulations by REACH (Registration, Evaluation, Authorization and Restriction of Chemical) on the safe use and traceability of chemicals used in the European Union.

The European Union's REACH legislation is intended as a comprehensive safety evaluation for commercial chemicals used in consumer products that are traded in Europe at amounts more than one ton per year. S ince June 1, 2007, REACH aims at pushing the industry to manage the risks posed by chemicals and providing appropriate safety information to those who use them. Thus our new chemical compound would be a product as of June 1, 2008, that would need to be registered through the European Chemicals Agency. If our new chemical compound met the definition of phase-in substances then it would have to be pre-registered between June 1 and December 1, 2008.

From 2007 through 2010 will be key strategic years for all companies that are producing, importing and using chemicals. Especially new chemical compounds synthesised for use of insecticides in particular TCCD and its human toxicity implication to health disorders. The implementation of REACH (and in parallel GHS) requires companies to prepare for and manage a huge number of internally and externally focused activities. These ranges from raw material and chemical products review, data and testing gap analysis, current and future classification & labeling, identification of all uses of a substance, up to the proceeding of the strategic planning. The latter includes identifying any opportunities for exemption from REACH, obtaining derogations from testing due to low concern/exposure,or justifying chemical groupings and read-across strategies for specific environmental behaviour, exposure scenarios or toxicological endpoints. Moreover, pre-registration and registration is required and the completion of Chemical Safety Assessments.

However, implementation of the regulation may require 54 million research animals and approximately ($13.4 billion) over the next 10 years, which represents 20 times the number of animals and six times the cost anticipated in previous estimates, according to an analysis led by researchers at the Johns Hopkins Bloomberg School of Public Health. Currently, the EU uses approximately 900,000 animals at a cost of approximately ($847 million) per year to evaluate new chemicals, drugs, pesticides and food additives

**Conclusion:**

I cannot find a better summary as was articulated by the EU Environment Commissioner Stavros Dimas on toxic effects from chemical products on man and the environment about REACH who said:

//“This agreement will represent a marked improvement in the protection of health and the environment. It will reduce chemical related disease and will allow users and consumers to make informed choices about the substances they come in contact with. It will also encourage __innovation__ and give a strong incentive to industry to replace dangerous chemicals with safer ones. The agreement presents to our citizens a chance for a healthier life and a safer environment.//”

Suffice to say there are companies that have now become innovative in ways of improving the toxicity effects on biota one such company is BioPesTech which announces a breakthrough in natural insecticides and claims that the new non-toxic insecticide technology is highly effective and harmless to humans. BioPesTech's natural insecticide technology works by targeting the chemoreceptors of insects.Blocking these important chemoreceptors (a complex group of proteins that determine insect behaviour and survival) deregulates the intracellular signalling, thereby either repelling or killing the insects. Using their biochemical expertise, BioPesTech, in partnership with Dr Essam Enan, a renowned biochemist and toxicologist at Vanderbilt University's School of Medicine, has cloned these insect receptors and has developed a proprietary screening methodology. BioPesTech has shown that selected GRAS (generally regarded as safe) natural oils bind tightly to insect chemoreceptors. Although this phenomenon has been known for many years and insect repellents have been made using these oils, BioPesTech's technology enables it to predict and measure both the binding efficiency of the oils to the insect's receptors and the downstream signalling events that happen inside the cell. This has allowed BioPesTech to discover natural oil combinations or mixes that produce a large synergistic effect on specific insects. Formulations can be optimised for certain types of insects and can also be designed to either repel or kill the insects. These results also demonstrate the success and efficacy of BioPesTech's technology platform which has been designed to create a new category of both effective and safe insecticides.

As we are aware the EU has recently banned hundreds of chemicals that are the active ingredients in most 'traditional' pesticides, resulting in an immediate need for new, non-toxic insecticides such as the BioPesTech formula. The global market for insecticides and pesticides is currently estimated to be worth more than US $30 billion per year. BioPesTech is currently in the advanced development phase for the insecticide formula and is involved in licensing and distribution discussions with a number of global consumer product companies. Maybe we might just hold off on our new chemical compound which has been synthesisied as an insecticide and maybe invest with BIoPesTech new insecticideformula.

ACGIH, 2004. Threshold Limit Values for chemical substances and physical agents. Biological Exposure Indices. U.S. American Conference ofGovernmental Industrial Hygienists (ACGIH), Cincinatti, OH, USA. ( [] ).
 * Bibliography **

[1] LD50 is the abbreviation used for the dose which kills 50% of the test population [2] Chapter 3 · Food, Diet, Nutrition and Contaminants AMAP report

[3] (Cohen, 1997b), [4] [] [5] ( [|WHO, 1993] ; [|WHO, 1996] and [|WHO, 1998] ). [6] Evaluated by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), the ADI thus derived was employed.