4Methods for Toxicity TestingT HE PURPOSE OF THIS CHAPTER is to familiarize the reader with the testing that is currently conducted by a manufacturer prior to and during the process of submitting a petition to register a pesticide. Codified toxicologic evaluation of potential pesticides has been a requirement in the United States for approximately 50 years. The testing requirements and guidelines continue to evolve based on new science. This chapter identifies the current testing that is pertinent to the young animal and young human as well as aspects of testing that are needed to fill the data gaps to better ensure the protection of infants and children. The current testing guidelines can be found in Pesticide Assessment Guidelines issued by the Environmental Protection Agency (EPA, 1991a,b).Data, including those derived from toxicity testing, crop residue analyses, environmental fate testing, and ecotoxicology testing, are generated by the manufacturer of a pesticide to meet the mandatory requirements of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) for pesticide registration. Although these data are essential to the EPA's registration process, other data generated by EPA itself, as well as by other government institutions and academia, are considered in the registration decision-making process.EPA has issued 194 registration standards on 350 chemicals used as active and inert ingredients in pesticide products.
These standards are published by EPA and are intended to upgrade and update the data base on a previously registered pesticide or class of pesticide products. They call for additional studies in the areas of toxicity testing, crop residue analyses, environmental fate, and ecotoxicology testing.
A foodborne outbreak investigation goes through several steps. They are described here in order, but in reality investigations are dynamic and several steps may happen at the same time. Click on each step to learn more about the investigation process. Finding sick people is important to help public. Emergency Response with Phast. These equipment items can be placed in a map which may also include Geographical Information System (GIS) – layers of information with, for example, the location of population area, control-room, accommodations, and specific areas of the plan where expensive equipment items are located.
This testing must be conducted within an EPA-mandated time frame to allow for the continued. CURRENT METHODS: GENERAL CONSIDERATIONSToxicity studies are required to assess potential hazards to humans through the acute, subchronic, and chronic exposure of laboratory animals to pesticides. The more specific types of toxicity that are determined include carcinogenicity; developmental (including teratogenicity in offspring) and reproductive toxicity; mutagenicity; and neurotoxicity. Detailed information on the metabolism or biotransformation of the pesticide is also obtained. Consideration is given to testing individual metabolites in animals, and in or on pesticide-treated plants to which humans could exposed through their diet. The extent of metabolite testing required depends on the level of potential toxicity and environmental persistence of the metabolite.
With the exception of. The acute toxicity tests, most tests are conducted to determine the nature of any toxicity that can be produced by repeatedly dosing animals over an extended period. The results enable toxicologists to estimate the safety of a material of humans (Loomis, 1978).Weil (1972) published the following set of guidelines, which reflected a consensus among toxicologists.
These should be considered before initiating a toxicity test:.Use, wherever practical or possible, one or more species that biologically handle the material qualitatively and/or quantitatively as similarly as possible to man. For this, metabolism, absorption, excretion, storage and other physiological effects might be considered.Where practical, use several dose levels on the principle that all types of toxicologic and pharmacologic actions in man and animals are dose-related. The only exception to this should be the use of a single, maximum dosage level if the material is relatively nontoxic; this level should be a sufficiently large multiple of that which is attainable by the applicable hazard exposure route, and should not be physiologically impractical.Effects produced at higher dose levels (within the practical limits discussed in 2) are useful for delineating mechanism of action, but for any material effect, some dose level exists for man or animal below which this adverse effect will not appear. This biologically insignificant level can and should be set by use of a proper uncertainty factor and competent scientific judgment.Statistical tests for significance are valid only on the experimental units (e.g., either litters or individuals) that have been mathematically randomized among the dosed and concurrent control groups.Effects obtained by one route of administration to test animals are not a priori applicable to effects by another route of administration to man. The routes chosen for administration to test animals should, therefore, be the same as those to which man will be exposed. Thus, for example, food additives for man should be tested by admixture of the material in the diet of animals.In general, Weil's guidelines are considered by EPA in its toxicity testing requirements and subsequent evaluation of results for pesticides.
One exception to Weil's points is found in his guideline 3. EPA does not recognize the existence of a dose level at which a carcinogen will not exert its effect. For carcinogens, EPA generally accepts a risk of 10 -6, as extrapolated from bioassays using the nonthreshold modification of the linearized multistage model of Armitage and Doll (1954), as adequate for the protection of humans.The selection of animal species for toxicity tests depends on life span. Behavior, availability, and overall costs. EPA recommends using rats for subchronic, chronic, carcinogenicity, and reproduction studies; mice for carcinogenicity studies; and dogs for subchronic and chronic studies. Rats are routinely used for acute oral and inhalation studies and rabbits for eye and skin irritation studies and acute dermal studies.
One exception to this is the use of guinea pigs for dermal sensitization testing. The rat and rabbit are recommended for developmental toxicity (teratogenicity) testing.
Justification must be provided for the use of species other than those outlined above.The number of animals to be tested in each dose group depends on a number of factors, including the purpose of the experiment, the required sensitivity of the study, the reproductive capacity and the fertility of the species, economic aspects, and the availability of animals (IPCS, 1990). Lists the minimum number of animals required by EPA for some toxicity studies. For the most part, these numbers are consistent with those recommended by the International Program Chemical Safety (IPCS).The selection of dose levels for subchronic studies should be based on the results of acute toxicity testing, on range-finding studies, and on pharmacokinetic (metabolism, including rate in various tissues) data. For subchronic studies, four dose groups of animals should be included: a control group; a low-dose group (a dose that produces no compound related toxicity); a mid-dose group (a dose that elicits some minimal signs of toxicity); and a high-dose group (a dose that results in toxic effects but not in an incidence of fatalities that would prevent a meaningful evaluation; for nonrodents, there should be no fatalities) (EPA, 1984). This same guidance is relevant to chronic toxicity and reproduction studies.
For teratology studies, the highest dose tested should elicit some signs of maternal toxicity, but the toxicity should not obscure the results.The one notable exception to this guidance pertains to carcinogenicity studies. The highest dose levels for these studies should be at a maximum tolerated dose (MTD), as determined in 90-day toxicity studies in the appropriate test species and from pharmacokinetic information on the material being tested. The Committee on Risk Assessment Methodology of the National Research Council (NRC) recently examined the criteria for the MTD and other doses used in carcinogenicity studies (NRC, 1993).
The EPA has issued its own guidance for the selection of this dose level. Some of the factors to consider in selecting an MTD are: 10% decrement in body weight gain in 90-day study; observation of potential life-threatening lesions during microscopic examination of organs, e.g., liver necrosis; significant inhibition of cholinesterase activity in two biological compartments, such as brain and plasma; and significant signs of anemia or other biologically relevant effects on blood.
TABLE 4-2 Animal Model Requirements in Toxicity StudiesMinimum No. Given to the test animals in their diet, dosing is usually continuous for 7 days a week. If the material is administered by gavage (oral bolus dose), by dermal application, or by inhalation, doses are frequently given 5 days a week, which is acceptable to EPA because of practical considerations (EPA, 1984).The type of statistical analysis performed on the toxicity data resulting from these studies depends on the type of data under consideration (see, for example, Gad and Weil, 1982, for review). Interpreting the meaning of statistical significance for any particular parameter depends on the dose level at which it was achieved, the biological significance of the finding, and the normal spontaneous occurrence of this finding in the strain and species being tested.For regulatory purposes, the no-observed-effect level (NOEL) is defined as a dose level at which no effects attributable to the pesticide under test can be found. A no-observed-adverse-effect level (NOAEL) can also be determined for each study; however, EPA does not routinely use the NOAEL to regulate pesticide usage. To establish a NOAEL, the toxicologist must determine what is and what is not adverse effect, which can be defined differently by different scientists.
For example, effects such as hair loss can be considered adverse by some and not by others. Plasma and red blood cell cholinesterase inhibition can be viewed as either an adverse effect or simply as a market of exposure to a pesticide.EPA uses the NOEL to calculate the acceptable daily intake (ADI) of the pesticide under consideration.
More recently, the EPA has replaced the ADI with the reference dose, or RfD. Chronic studies, such as reproduction studies and lasting 1 year or longer in the rat or dog are used for this purpose. EPA does not routinely use the NOEL determined from teratology (developmental toxicity) studies for calculating ADIs because the observed effect are not considered chronic; however, these NOELs can be used to support the calculated ADI. EPA does routinely use developmental toxicity NOELs for other types of risk assessments, such as calculating the risk from acute, daily dietary or occupational exposure or from exposure of homeowners to a developmental toxicant.EPA's toxicity testing requirements for food and nonfood use pesticides have been published in 40 CFR Part 158. In general, for food use chemical with maximum human exposure, the following toxicity tests are required. carcinogenicity. developmental toxicity.
mutagenicity tests. general metabolism studyMore than 30% of the tests for pesticides submitted to EPA in the past have been rejected. Those rejected must be resubmitted until they are in conformance with EPA criteria before registrations can be granted. The criteria for rejection are summarized in. Some of them fall in the category of regulatory policy; others involve scientific concerns. The most commonly cited reason for noncompliance is lack of characterization of the test material.
To improve the quality of testing and incorporate new scientific methods in its testing requirements, EPA is currently revising the 40 CFR Part 158 data requirements for food and nonfood use pesticides. The proposed revisions to these requirements can be found in. General DescriptionAcute toxicity studies provide information on the potential for health hazards that may arise as result of short-term exposure. Determination of acute oral, dermal, and inhalation toxicity is usually the initial step in evaluating the toxic characteristics of a pesticide. In each of these tests the animal is exposed to the test material only once on 1 day. Together with information derived from primary eye and primary dermal irritation studies (also 1 dose on 1 day), which assess possible hazards resulting from pesticide contact with eyes and skin, these data provide a basis for precautionary labeling and may influence the classification of a pesticide for restricted use. Acute toxicity data also provide information used to determine the need for child-resistant packaging, for protective clothing requirements for applicator, and for calculation of farm worker reentry intervals.
A minimum number of animals, usually adults, are used in these studies and only the end points of concern are monitored, i.e., mortality, observable skin or eye effects, dermal sensitization, and observable neurotoxic behavioral changes. One exception is the inclusion of microscopic examination of neural tissues in the newly required acute neurotoxicity study. TABLE 4-3 Summary of EPA Rejection FactorsGuidelineRejection FactorAcute Oral Toxicity (81-1)Lack of characterization of the test materialInadequate dose levels to calculate LD 50Acute Dermal Toxicity (81-2)Lack of characterization of the test materialInadequate percentage of body surface area exposedNo quality assurance statementImproper number of animals tested per dose groupOnly one sex testedOmitted source, age, weight, or strain of test animalAcute and 90-Day Inhalation (81-3 and 82-4)Less than 25% of particles were. General DescriptionSubchronic exposures do not elicit effects that have a long latency period (e.g., carcinogenicity).
However, they do provide information on health hazards that may result from repeated exposures to a pesticide over a period up to approximately 30% of the lifetime of a rodent. Subchronic tests also provide information necessary to select proper dose levels for chronic studies, especially for carcinogenicity studies for which an MTD must be selected.
According to EPA (1984), rats selected for these studies should be started on the test material shortly after weaning, 'ideally before the rats are 6 and, in any case, not more than 8 weeks old.' For dogs, dosing should begin when they are 4 to 6 months of age and 'not later than 9 months of age.' Most subchronic toxicity studies monitor clinical or behavioral (neurological) signs of toxicity, body weight, food consumption, eye effects, certain plasma or serum and urine parameters, organ weights, and gross and microscopic pathology. Clinical and behavioral signs of toxicity are observed and recorded daily. They can consist of activity, gait, excreta, hair coat, and feeding and drinking patterns. Body weight and food consumption data are routinely recorded throughout the study at intervals (usually weekly) determined by the length of the study. Ophthalmoscopic examinations are conducted at the beginning of the study and, typically, just before it terminates.
The laboratory parameters typically examined are summarized in.The results of hematology testing indicate whether, for example, the chemical affects blood cell formation and survival, clotting factors, and platelets. Clinical chemistry and urinalysis results can indicate possible kidney, liver, pancreas, and cardiac function or toxicity as well as any electrolyte imbalance.
Urinalysis results can indicate adequacy of kidney, liver, and pancreas function.After necropsy, the weights of certain organs are also recorded. These organs generally include brain, gonads, liver, and kidneys, which are the four required according to EPA testing guidelines (EPA, 1984). If toxicity is known to occur in another organ from previous testing, the weight of this organ should also be reported. For thyroid toxicity, for example, the weight of the thyroids should be recorded.
Changes from untreated control animals are generally an indication of potential toxicity in this organ.A complete necropsy is performed after sacrifice or death of the test animal. Generally all tissues are examined, and those saved for microscopic examination are aorta, jejunum, peripheral nerve, eyes, bone marrow, kidneys, cecum, liver, esophagus, colon, lung, ovaries, duodenum. Notes for Table 4-4: Specific Conditions, Qualifications, or Exceptions to the Designated Test Procedures1. Not required if test material is a gas or highly volatile.2. Not required if test material is corrosive to skin or has pH 11.5; such a product will be classified as toxicity category 1 on the basis of potential eye and dermal irritation effects.3. Required when the product consists of, or under conditions of use will result in, an inhalable material (e.g., gas, volatile substances, or aerosol/particulate).4.
Required unless repeated dermal exposure does not occur under conditions of use.5. Required for uncharged organophosphorus esters, thioesters, or anhydrides of organophosphoric, organophosphonic, or organophosphoramidic acids or of related phosphorothioic, phosphonothioic, or phosphorothioamidic acids, or other substances that may cause the neurotoxicity sometimes seen in this class.6. Additional measurements such as cholinesterase determinations for certain pesticides (e.g., organophosphates and carbamates) may also be required.
The route of exposure should correspond to a primary route of human exposure.7. Required if intended use of the pesticide is expected to result in human exposure via the oral route.8. All 90-day subchronic studies can be designed to simultaneously fulfill the requirements of the 90-day neurotoxicity study.9. Studies must include additional end points so as to provide an immunotoxicity screen in the rodent. An equivalent independent study may fulfill the requirements for an immunotoxicity screen.10. In most cases, where the theoretical maximum residue contribution (TMRC) exceeds 50 percent of the reference dose (Rfd), a 1-year (or longer) interim report on a chronic (2-year) feeding study is required to support a temporary tolerance.
This report is to be in addition to the 90-day feeding studies in rodents and nonrodents.11. If the pesticide is found to leach into groundwater or may contaminate drinking water, a 90-day drinking water study may be required unless data demonstrate that there are no significant differences in toxicity observed when the test material is administered in feed versus when the test material is administered in drinking water. This study may be requested in addition to any 90-day oral studies that may be required.12. Required if intended use of the pesticide is expected to result in human exposure via the dermal route and data from a subchronic 90-day dermal toxicity study are not required.13. For nonfood uses, a 90-day dermal toxicity study is required, since intended use of the pesticide is expected to result in repeated dermal exposure of humans.
For food uses, required if: (a) the active ingredient of the product is known or expected to be metabolized differently by the dermal route of exposure than by the oral route, and a metabolite of the active ingredient is the toxic moiety; (b) the active ingredient of the product is classified as toxicity category I or II on the basis of acute dermal toxicity data.15. Required if the active ingredient is a gas at room temperature or if use of the product results in respirable droplets and use may result in repeated inhalation exposure at a concentration likely to be toxic, regardless of whether the major route of exposure is inhalation16.
Required for substances when statistically or biologically significant effects were seen in the acute study (Guideline 81-7), or if other available data indicate that the substance can cause this type of delayed neurotoxicity.17. Required if either of the following criteria is met: (a) use of the pesticide is likely to result in repeated human exposure over a significant portion of the human life span (e.g., products intended for use in and around residences, swimming pools, and enclosed working spaces or their immediate vicinity); (b) the use requires a tolerance for the pesticide or an exemption from the requirement to obtain a tolerance for the pesticide or an exemption from the requirement to obtain a tolerance, or requires issuance of a food additive regulation.18. Based on acute and subchronic neurotoxicity studies, and/or on other available data, a functional observational battery, an assessment of motor activity, and perfusion neuropathology may be required.19. Studies designed to simultaneously fulfill the requirements of both the chronic feeding and carcinogenicity studies (i.e., a combined study) may be conducted.
Minimum acceptable study durations for chronic feeding and carcinogenicity studies are as follows: chronic rodent feeding study (food use pesticide)—24 months; chronic rodent feeding study (nonfood pesticide)—12 months in usually sufficient; chronic nonrodent (i.e. Dog) feeding study—12 months; mouse carcinogenicity study-18 months; and rat carcinogenicity study—24 months.20. Required active ingredients or any of their metabolites, degradation products, or impurities are structurally related to a recognized carcinogen, cause mutagenic effects as demonstrated by in vitro or in vivo testing, or produce a morphologic effect in any organ (e.g., hyperplasia, metaplasia) in subchronic studies that may lead to neoplastic change. The use requires a tolerance for the pesticide or exemption from the requirement to obtain a tolerance or requires the issuance of a food additive regulation. Use of the pesticide product is likely to result in exposure of humans over a portion of the life span that is significant in terms of either the timing or duration of exposure (e.g., pesticides used in treated fabrics for wearing apparel, diapers, or bedding; insect repellents applied directly to the skin; swimming pool additives; or constant-release indoor aerosol pesticides).21. Range-finding studies of at least 90 days duration in rats and mice are generally required to determine dose levels adequate to demonstrate an MTD in carcinogenicity studies.
A subchronic 90-day oral study conducted in accordance with Guideline 82-1 may also be acceptable for this purpose. Testing in two species is required for food uses. For products intended for nonfood uses, testing in two species is required if significant exposure of human females of child-bearing age may reasonably be expected. For other nonfood uses, testing in at least one species is required. A study in one species is required to support a temporary tolerance.23. Testing in a second species is required if significant developmental toxicity is observed after testing in the first species.24.
The test substance or vehicle is usually administered by oral intubation, unless the chemical or physical characteristics of the test substance or pattern of human exposure suggest.
Coordinating a ionCrown ethers are cyclic that consist of a ring containing several groups. The most common crown ethers are cyclic of, the repeating unit being ethyleneoxy, i.e., –CH 2CH 2O–.
Important members of this series are the tetramer ( n = 4), the pentamer ( n = 5), and the hexamer ( n = 6). The term 'crown' refers to the resemblance between the structure of a crown ether bound to a, and a sitting on a person's head. The first number in a crown ether's name refers to the number of atoms in the cycle, and the second number refers to the number of those atoms that are. Crown ethers are much broader than the of ethylene oxide; an important group are derived from.Crown ethers strongly bind certain cations, forming. The oxygen atoms are well situated to coordinate with a cation located at the interior of the ring, whereas the exterior of the ring is hydrophobic. The resulting cations often form salts that are soluble in nonpolar solvents, and for this reason crown ethers are useful in.
The of the polyether influences the affinity of the crown ether for various cations. For example, 18-crown-6 has high affinity for potassium cation, 15-crown-5 for sodium cation, and 12-crown-4 for lithium cation.
The high affinity of 18-crown-6 for potassium ions contributes to its toxicity. Crown ethers are not the only macrocyclic ligands that have affinity for the potassium cation. Such as also display a marked preference for the potassium cation over other cations.Crown ethers have been shown to coordinate to through electrostatic, σ-hole (see ) interactions, between the Lewis basic oxygen atoms of the crown ether and the electrophilic Lewis acid center. Contents.History In 1967, who was a working at, discovered a simple method of synthesizing a crown ether when he was trying to prepare a for. His strategy entailed linking two groups through one on each molecule. This linking defines a polydentate ligand that could partially envelop the cation and, by of the phenolic hydroxyls, neutralize the bound dication. He was surprised to isolate a that strongly complexed cations.
Citing earlier work on the dissolution of in 16-crown-4, he realized that the cyclic represented a new class of complexing agents that were capable of binding cations. He proceeded to report systematic studies of the synthesis and binding properties of crown ethers in a seminal series of papers. The fields of, and other emerging disciplines benefited from the discovery of crown ethers. Pedersen particularly popularized the dibenzo crown ethers.
Catenane derived from cyclobis(paraquat-p-phenylene)(a cyclophane with two viologen units) and a cyclic polyether (bis(para-phenylene-34-crown-10)). Carbon atoms of the two rotaxane components are colored green and purple. Otherwise, O = red, N = blue. H atoms are omitted.
The second of Nobel Prizes in Chemistry involving crown ethers was awarded for the design and synthesis of molecular machines. Many of these 'machines' incorporate crown ethers as essential design components.Pedersen shared the 1987 for the discovery of the synthetic routes to, and binding properties of, crown ethers.Affinity for cations Apart from its high affinity for potassium cations, can also bind to protonated amines and form very stable complexes in both solution and the gas phase. Some, such as, contain a primary on their side chains.
Those protonated amino groups can bind to the cavity of 18-crown-6 and form stable complexes in the gas phase. Hydrogen-bonds are formed between the three hydrogen atoms of protonated amines and three oxygen atoms of 18-crown-6. These hydrogen-bonds make the complex a stable adduct. By incorporating luminescent substituents into their backbone, these compounds have proved to be sensitive ion probes, as changes in the absorption or fluorescence of the photoactive groups can be measured for very low concentrations of metal present.
Some attractive examples include macrocycles, incorporating oxygen and/or nitrogen donors, that are attached to polyaromatic species such as anthracenes (via the 9 and/or 10 positions) or naphthalenes (via the 2 and 3 positions). Azacrowns 21- and 18-membered diazacrown ether derivatives exhibit excellent and selectivities and are widely used in. Some or all of the oxygen atoms in crown ethers can be replaced by nitrogens to form. A well-known tetrazacrown is in which there are no oxygens.crown ethers have sidearms that can augment complexation of cation. The lariat is typically attached to an amine centre in an azacrown.
See also.References. Marczenko, K. M.; Mercier, H.
A.; Schrobilgen, G. 'A Stable Crown-Ether Complex with a Noble-gas Compound'. 57 (38): 2. Lipkowski, J.; Fonari, M. S.; Kravtsov, V.
C.; Simonov, Y. A.; Ganin, E.
V.; Gemboldt, V. 'Antimony(III) fluoride: Inclusion complexes with crown ethers'. 26 (12): 823. Pedersen, C.
'Cyclic polyethers and their complexes with metal salts'. Journal of the American Chemical Society. 89 (26): 7017–7036. Pedersen, C.
'Cyclic polyethers and their complexes with metal salts'. Journal of the American Chemical Society. 89 (10): 2495–2496., Stewart, D. Borrows, issued 1957-10-23. Down, J.
L.; Lewis, J.; Moore, B.; Wilkinson, G. The solubility of alkali metals in ethers'. Journal of the Chemical Society: 3767. Pedersen, Charles J. (1988).; Collective Volume, 6, p. 395.
Ashton, P. R.; Goodnow, T. T.; Kaifer, A. E.; Reddington, M. V.; Slawin, A. Z.; Spencer, N.; Stoddart, J. F.; Vicent, C.; Williams, D.
'A 2 Catenane Made to Order'. Angewandte Chemie International Edition in English. 28 (10): 1396–1399. CS1 maint: uses authors parameter. Fabbrizzi, L.; Francese, G.; Licchelli, M.; Pallavicini, P.; Perotti, A.; Poggi, A.; Sacchi, D.; Taglietti, A. Desvergne, J. P.; Czarnik, A.
Chemosensors of Ion and Molecule Recognition. NATO ASI Series C. Dordrecht: Kluwer Academic Publishers. P. 75.
Bouas-Laurent, H.; Desvergne, J. P.; Fages, F.; Marsau, P. W., Czarnik (ed.). Fluorescent Chemosensors for Ion and Molecule Recognition.
ACS Symposium Series 538. Washington, DC: American Chemical Society. P. 59. Sharghi, Hashem; Ebrahimpourmoghaddam, Sakineh (2008). 'A Convenient and Efficient Method for the Preparation of Unique Fluorophores of Lariat Naphtho-Aza-Crown Ethers'. Helvetica Chimica Acta. 91 (7): 1363–1373.
Suzuki, K.; Watanabe, K.; Matsumoto, Y.; Kobayashi, M.; Sato, S.; Siswanta, D.; Hisamoto, H. 'Design and Synthesis of Calcium and Magnesium Ionophores Based on Double-Armed Diazacrown Ether Compounds and Their Application to an Ion Sensing Component for an Ion-Selective Electrode'. 67 (2): 324–334. Gatto, Vincent J.; Miller, Steven R.; Gokel, George W. (1988).; Collective Volume, 8, p. 152.
Gokel, G. W.; Barbour, L. J.; Ferdani, R.; Hu, J.
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'Lariat Ether Receptor Systems Show Experimental Evidence for Alkali Metal Cation Interactions'. 35 (10): 878–886.External links Wikimedia Commons has media related to. Pedersen, Charles (1987). Nobel Prize.