Reference dose

Last updated

A reference dose is the United States Environmental Protection Agency's maximum acceptable oral dose of a toxic substance, "below which no adverse noncancer health effects should result from a lifetime of exposure". Reference doses have been most commonly determined for pesticides. The EPA defines an oral reference dose (abbreviated RfD) as:

Contents

[A]n estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. [1]

Definition

The United States Environmental Protection Agency defines a reference dose (abbreviated RfD) as the maximum acceptable oral dose of a toxic substance, below which no adverse non cancerous health effects should result from a lifetime of exposure. It is an estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. [1]

Regulatory status

RfDs are no enforceable standards, unlike National Ambient Air Quality Standards. RfDs are risk assessment benchmarks, and the EPA tries to set other regulations, so that people are not exposed to chemicals in amounts that exceed RfDs. According to the EPA from 2008, "[a]n aggregate daily exposure to a [chemical] at or below the RfD (expressed as 100 percent or less of the RfD) is generally considered acceptable by EPA." [2] States can set their own RfDs.

For example, the EPA set an acute RfD for children of 0.0015 mg/kg/day for the organochlorine insecticide endosulfan, based on neurological effects observed in test animals. The EPA then looked at dietary exposure to endosulfan, and found that for the most exposed 0.1 % of children age 1–6, their daily consumption of the endosulfan exceeded this RfD. To remedy this, the EPA revoked the use of endosulfan on the crops that contributed the most to exposure of children: certain beans, peas, spinach, and grapes. [3]

Types

Reference doses are chemical-specific, i.e. the EPA determines a unique reference dose for every substance it evaluates. Often separate acute (0-1 month)and chronic RfDs (more than one month) are determined for the same substance. Reference doses are specific to dietary exposure. When assessing inhalation exposure, EPA uses "reference concentrations" (RfCs), instead of RfDs. Note that RfDs apply only to non-cancer effects. When evaluating carcinogenic effects, the EPA uses the Q1* method.

Determination

RfDs are usually derived from animal studies. Animals (typically rats) are dosed with varying amounts of the substance in question, and the largest dose at which no effects are observed is identified. This dose level is called the No observable effect level, or NOEL. To account for the fact that humans may be more or less susceptible than the test animal, a 10-fold "uncertainty factor" is usually applied to the NOEL. This uncertainty factor is called the "interspecies uncertainty factor" or UFinter. An additional 10-fold uncertainty factor, the "intraspecies uncertainty factor" or UFintra, is usually applied to account for the fact that some humans may be substantially more sensitive to the effects of substances than others. Additional uncertainty factors may also be applied. In general:

Frequently, a "lowest-observed-adverse-effect level" or LOAEL is used in place of a NOEL. If adverse effects are observed at all dose levels tested, then the smallest dose tested, the LOAEL, is used to calculate the RfD. An additional uncertainty factor usually applied in these cases, since the NOAEL, by definition, would be lower than the LOAEL had it been observed. If studies using human subjects are used to determine a RfD, then the interspecies uncertainty factor can be reduced to 1, but generally the 10-fold intraspecies uncertainty factor is retained. Such studies are rare.

Example

As an example, consider the following determination of the RfD for the insecticide chlorpyrifos, adapted from the EPA's Interim Reregistration Eligibility Decision for chlorpyrifos. [4]

The EPA determined the acute RfD to be 0.005 mg/kg/day based on a study in which male rats were administered a one-time dose of chlorpyrifos and blood cholinesterase activity was monitored. Cholinesterase inhibition was observed at all dose levels tested, the lowest of which was 1.5 mg/kg. This level was thus identified at the lowest observed adverse effect level (LOAEL). A NOAEL of 0.5 mg/kg was estimated by dividing the LOAEL by a three-fold uncertainty factor. The NOAEL was then divided by the standard 10-fold inter- and 10-fold intraspecies uncertainty factors to arrive at the RfD of 0.005 mg/kg/day. Other studies showed that fetuses and children are even more sensitive to chlorpyrifos than adults, so the EPA applies an additional ten-fold uncertainty factor to protect that subpopulation. A RfD that has been divided by an additional uncertainty factor that only applies to certain populations is called a "population adjusted dose" or PAD. For chlorpyrifos, the acute PAD (or "aPAD") is thus 5×10−4 mg/kg/day, and it applies to infants, children, and women who are breast feeding.

The EPA also determined a chronic RfD for chlorpyrifos exposure based on studies in which animals were administered low doses of the pesticide for two years. Cholinesterase inhibition was observed at all dose levels tested, and a NOAEL of 0.03 mg/kg/day estimated by dividing a LOAEL of 0.3 mg/kg/day by an uncertainty factor of 10. As with the acute RfD, the chronic RfD of 3×10−4 mg/kg/day was determined by dividing this NOAEL by the inter- and intraspecies uncertainty factors. The chronic PAD ("cPAD") of 3×10−5 mg/kg/day was determined by applying an additional 10-fold uncertainty factor to account for the increased susceptibility of infants and children. Like the aPAD, this cPAD applies to infants, children, and breast feeding women.

Consensus

Because the RfD assumes "a dose below which no adverse noncarcinogenic health effects should result from a lifetime of exposure", [5] the critical step in all chemical risk and regulatory threshold calculations is dependent upon a properly derived dose at which no observed adverse effects (NOAEL) were seen which is then divided by an uncertainty factor that considers inadequacies of the study, animal-to-human extrapolation, sensitive sub-populations, and inadequacies of the database. The RfD that is derived is not always agreed upon. Some may believe it to be overly protective while others may contend that it is not adequately protective of human health.

For example, in 2002 the EPA completed its draft toxicological review of perchlorate and proposed an RfD of 0.00003 milligrams per kilogram per day (mg/kg/day) based primarily on studies that identified neurodevelopmental deficits in rat pups. These deficits were linked to maternal exposure to perchlorate. Subsequently, the National Academy of Sciences (NAS) reviewed the health implications of perchlorate, and in 2005 proposed a much higher alternative reference dose of 0.0007 mg/kg/day based primarily on a 2002 study by Greer et al. [6] During that study, 37 adult human subjects were split into four exposure groups exposed to 0.007 (7 subjects), 0.02 (10 subjects), 0.1 (10 subjects), and 0.5 (10 subjects) mg/kg/day. Significant decreases in iodide uptake were found in the three highest exposure groups. Iodide uptake was not significantly reduced in the lowest exposed group, but four of the seven subjects in this group experienced inhibited iodide uptake. In 2005, the RfD proposed by NAS was accepted by EPA and added to its integrated risk information system (IRIS).

In a 2005 article in the journal Environmental Health Perspectives (EHP), Gary Ginsberg and Deborah Rice argued, that the 2005 NAS RfD was not protective of human health based on the following: [7]

  1. The NAS report described the level of lowest exposure from Greer et al. as a NOEL. However, there was actually an effect at that level although not statistically significant largely due to small size of study population (four of seven subjects showed a slight decrease in iodide uptake).
  2. Reduced iodide uptake was not considered to be an adverse effect even though it is a precursor to an adverse effect, hypothyroidism. Therefore, additional safety factors, they argued, are necessary when extrapolating from the point of departure to the RfD.
  3. Consideration of data uncertainty was insufficient because the Greer, et al. study reflected only a 14-day exposure ( acute) to healthy adults and no additional safety factors were considered to protect sensitive subpopulations like for example, breastfeeding newborns.

Although there has generally been consensus with the Greer et al. study, there is no consensus with regard to developing a perchlorate RfD. One of the key differences results from how the point of departure is viewed (i.e., NOEL or LOAEL), or whether a benchmark dose should be used to derive the RfD. Defining the point of departure as a NOEL or LOAEL has implications when it comes to applying appropriate safety factors to the point of departure to derive the RfD. [8]

In 2010, the Massachusetts Department of Environmental Protection set a 10 fold lower RfD (0.07 μg/kg/day) using a much higher uncertainty factor of 100. They also calculated an Infant drinking water value, which neither US EPA nor CalEPA have done. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Perchlorate</span> Ion, and compounds containing the ion

A perchlorate is a chemical compound containing the perchlorate ion, ClO−4, the conjugate base of perchloric acid. As counterions, there can be metal cations, quaternary ammonium cations or other ions, for example, nitronium cation.

<span class="mw-page-title-main">Nuclear fission product</span> Atoms or particles produced by nuclear fission

Nuclear fission products are the atomic fragments left after a large atomic nucleus undergoes nuclear fission. Typically, a large nucleus like that of uranium fissions by splitting into two smaller nuclei, along with a few neutrons, the release of heat energy, and gamma rays. The two smaller nuclei are the fission products..

<span class="mw-page-title-main">Imidacloprid</span> Chemical compound

Imidacloprid is a systemic insecticide belonging to a class of chemicals called the neonicotinoids which act on the central nervous system of insects. The chemical works by interfering with the transmission of stimuli in the insect nervous system. Specifically, it causes a blockage of the nicotinergic neuronal pathway. By blocking nicotinic acetylcholine receptors, imidacloprid prevents acetylcholine from transmitting impulses between nerves, resulting in the insect's paralysis and eventual death. It is effective on contact and via stomach action. Because imidacloprid binds much more strongly to insect neuron receptors than to mammal neuron receptors, this insecticide is more toxic to insects than to mammals.

<span class="mw-page-title-main">Chlorpyrifos</span> Chemical compound

Chlorpyrifos (CPS), also known as chlorpyrifos ethyl, is an organophosphate pesticide that has been used on crops, animals, and buildings, and in other settings, to kill several pests, including insects and worms. It acts on the nervous systems of insects by inhibiting the acetylcholinesterase enzyme. Chlorpyrifos was patented in 1966 by Dow Chemical Company.

Acceptable daily intake or ADI is a measure of the amount of a specific substance in food or drinking water that can be ingested (orally) daily over a lifetime without an appreciable health risk. ADIs are expressed usually in milligrams per kilograms of body weight per day.

<span class="mw-page-title-main">Potassium iodide</span> Ionic compound (KI)

Potassium iodide is a chemical compound, medication, and dietary supplement. It is a medication used for treating hyperthyroidism, in radiation emergencies, and for protecting the thyroid gland when certain types of radiopharmaceuticals are used. In the third world it is also used for treating skin sporotrichosis and phycomycosis. It is a supplement used by people with low dietary intake of iodine. It is administered orally.

<span class="mw-page-title-main">Potassium perchlorate</span> Chemical compound

Potassium perchlorate is the inorganic salt with the chemical formula KClO4. Like other perchlorates, this salt is a strong oxidizer when the solid is heated at high temperature although it usually reacts very slowly in solution with reducing agents or organic substances. This colorless crystalline solid is a common oxidizer used in fireworks, ammunition percussion caps, explosive primers, and is used variously in propellants, flash compositions, stars, and sparklers. It has been used as a solid rocket propellant, although in that application it has mostly been replaced by the more performant ammonium perchlorate.

Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time. To be described as acute toxicity, the adverse effects should occur within 14 days of the administration of the substance.

<span class="mw-page-title-main">Atrazine</span> Herbicide

Atrazine is a chlorinated herbicide of the triazine class. It is used to prevent pre-emergence broadleaf weeds in crops such as maize (corn), soybean and sugarcane and on turf, such as golf courses and residential lawns. Atrazine's primary manufacturer is Syngenta and it is one of the most widely used herbicides in the United States, Canadian, and Australian agriculture. Its use was banned in the European Union in 2004, when the EU found groundwater levels exceeding the limits set by regulators, and Syngenta could not show that this could be prevented nor that these levels were safe.

<span class="mw-page-title-main">2,4,5-Trichlorophenoxyacetic acid</span> Chemical compound

2,4,5-Trichlorophenoxyacetic acid, a synthetic auxin, is a chlorophenoxy acetic acid herbicide used to defoliate broad-leafed plants. It was developed in the late 1940s, synthesized by reaction of 2,4,5-Trichlorophenol and chloroacetic acid. It was widely used in the agricultural industry until being phased out, starting in the late 1970s due to toxicity concerns. Agent Orange, a defoliant used by the British in the Malayan Emergency and the U.S. in the Vietnam War, was equal parts 2,4,5-T and 2,4-D. 2,4,5-T itself is toxic with a NOAEL of 3 mg/kg/day and a LOAEL of 10 mg/kg/day. Agent Pink contained 100% 2,4,5-T. Additionally, the manufacturing process for 2,4,5-T contaminates this chemical with trace amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is a carcinogenic persistent organic pollutant with long-term effects on the environment. With proper temperature control during production of 2,4,5-T, TCDD levels can be held to about .005 ppm. Before the TCDD risk was well understood, early production facilities lacked proper temperature controls and individual batches tested later were found to have as much as 60 ppm of TCDD.

<span class="mw-page-title-main">Endosulfan</span> Chemical compound

Endosulfan is an off-patent organochlorine insecticide and acaricide that is being phased out globally. It became a highly controversial agrichemical due to its acute toxicity, potential for bioaccumulation, and role as an endocrine disruptor. Because of its threats to human health and the environment, a global ban on the manufacture and use of endosulfan was negotiated under the Stockholm Convention in April 2011. The ban took effect in mid-2012, with certain uses exempted for five additional years. More than 80 countries, including the European Union, Australia, New Zealand, several West African nations, the United States, Brazil, and Canada had already banned it or announced phase-outs by the time the Stockholm Convention ban was agreed upon. It is still used extensively in India and China despite laws against its use. It is also used in a few other countries. It is produced by the Israeli firm Makhteshim Agan and several manufacturers in India and China. On May 13, 2011, the India Supreme Court ordered a ban on the production and sale of endosulfan in India, pending further notice.

<span class="mw-page-title-main">Methoxychlor</span> Synthetic organochloride insecticide, now obsolete.

Methoxychlor is a synthetic organochloride insecticide, now obsolete. Tradenames for methoxychlor include Chemform, Maralate, Methoxo, Methoxcide, Metox, and Moxie.

<span class="mw-page-title-main">Phosmet</span> Organophosphate non-systemic insecticide

Phosmet is a phthalimide-derived, non-systemic, organophosphate insecticide used on plants and animals. It is mainly used on apple trees for control of codling moth, though it is also used on a wide range of fruit crops, ornamentals, and vines for the control of aphids, suckers, mites, and fruit flies.

An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.

<span class="mw-page-title-main">Methiocarb</span> Chemical compound

Methiocarb is a carbamate pesticide which is used as an insecticide, bird repellent, acaricide and molluscicide since the 1960s. Methiocarb has contact and stomach action on mites and neurotoxic effects on molluscs. Seeds treated with methiocarb also affect birds. Other names for methiocarb are mesurol and mercaptodimethur.

<span class="mw-page-title-main">Ethoprophos</span> Chemical compound

Ethoprophos (or ethoprop) is an organophosphate ester with the formula C8H19O2PS2. It is a clear yellow to colourless liquid that has a characteristic mercaptan-like odour. It is used as an insecticide and nematicide and it is an acetylcholinesterase inhibitor.

The Stoker Company is a producer and applier of pesticides and a crop dusting loading facility, located in Imperial County, California, approximately 25 miles from the Mexican border. It is currently listed as a Superfund site because pesticides developed and used there are considered a human health hazard due to long-term exposure that may cause adverse health effects. Beginning in 1966, operations have caused on-site and off-site pesticide contamination to surface soil, water, and air.

<span class="mw-page-title-main">Novaluron</span> Chemical compound

Novaluron, or (±)-1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoro- methoxyethoxy)phenyl]-3-(2,6-difluorobenzoyl)urea, is a chemical with pesticide properties, belonging to the class of insecticides called insect growth regulators. It is a benzoylphenyl urea developed by Makhteshim-Agan Industries Ltd.. In the United States, the compound has been used on food crops, including apples, potatoes, brassicas, ornamentals, and cotton. Patents and registrations have been approved or are ongoing in several other countries throughout Europe, Asia, Africa, South America, and Australia. The US Environmental Protection Agency and the Canadian Pest Management Regulatory Agency consider novaluron to pose low risk to the environment and non-target organisms and value it as an important option for integrated pest management that should decrease reliance on organophosphorus, carbamate and pyrethroid insecticides.

Tolerable weekly intake (TWI) estimates the amount per unit body weight of a potentially harmful substance or contaminant in food or water that can be ingested over a lifetime without risk of adverse health effects. TWI is generally preceded by "provisional" to indicate insufficient data exists, increasing uncertainty. The term TWI should be reserved for when there is a well-established and internationally accepted tolerance, backed by sound and uncontested data. Although similar in concept to tolerable daily intake (TDI), which is of the same derivation of acceptable daily intakes (ADIs), TWI accounts for contaminants that do not clear the body quickly and may accumulate within the body over a period of time. An example is heavy metals such as arsenic, cadmium, lead, and mercury. The concept of TWI takes into account daily variations in human consumption patterns.

Threshold dose is the minimum dose of drug that triggers minimal detectable biological effect in an animal. At extremely low doses, biological responses are absent for some of the drugs. The increase in dose above threshold dose induces an increase in the percentage of biological responses. Several benchmarks have been established to describe the effects of a particular dose of drug in a particular species, such as NOEL(no-observed-effect-level), NOAEL(no-observed-adverse-effect-level) and LOAEL(lowest-observed-adverse-effect-level). They are established by reviewing the available studies and animal studies. The application of threshold dose in risk assessment safeguards the participants in human clinical trials and evaluates the risks of chronic exposure to certain substances. However, the nature of animal studies also limits the applicability of experimental results in the human population and its significance in evaluating potential risk of certain substances. In toxicology, there are some other safety factors including LD50, LC50 and EC50.

References

  1. 1 2 "Integrated Risk Information System (IRIS) Glossary". IRIS Vocabulary Catalog. United States Environmental Protection Agency.
  2. ↑ "Reregistration Eligibility Decision for 1,3-Dichloropropene" (PDF). United States Environmental Protection Agency. Archived from the original (PDF) on 28 February 2008.
  3. ↑ "Reregistration Eliligibility Decision for Endosulfan" (PDF). United States Environmental Protection Agency. Archived from the original (PDF) on 24 January 2011.
  4. ↑ "Interim Reregistration Eligibility Decision for Chlorpyrifos" (PDF). United States Environmental Protection Agency. Archived from the original (PDF) on 5 February 2007.
  5. ↑ "Maximum Contaminant Levels and Health Advisory Levels" (PDF). U.S. Environmental Protection Agency. 30 September 1999. Archived from the original (PDF) on 2011-02-13. Retrieved 2012-06-28.
  6. ↑ Greer MA, Goodman G, Pleus RC, Greer SE (September 2002). "Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans". Environmental Health Perspectives. 110 (9): 927–937. doi:10.1289/ehp.02110927. PMC   1240994 . PMID   12204829.
  7. ↑ Ginsberg Gary, Deborah Rice; Rice, Deborah (September 2005). "The NAS Perchlorate Review: Questions Remain about the Perchlorate RfD". Environmental Health Perspectives. 113 (9): 1117–1119. doi:10.1289/ehp.8254. ISSN   0091-6765. PMC   1280387 . PMID   16140613.
  8. ↑ "EPA's Perchlorate Drinking Water Preliminary Remediation Goal (Prg)" (PDF). Office of Environmental Health Assessments. Washington State Department of Health. 13 July 2007. Archived from the original (PDF) on 3 March 2017.] [ dead link ]
  9. ↑ Zewdie T, Smith CM, Hutcheson M, West CR (January 2010). "Basis of the Massachusetts reference dose and drinking water standard for perchlorate". Environmental Health Perspectives. 118 (1): 42–48. doi:10.1289/ehp.0900635. PMC   2831965 . PMID   20056583.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.