LAB to LABEL
People in general have a poor concept of what it takes to bring an agricultural product to the farm. Many have misconceptions concerning toxicological and environmental testing, and government regulations and requirements. Only about one in 20,000 compounds pass testing from synthesis to field use. It undergoes some 120 separate toxicological and environmental tests, ensuring that the compound poses no health or environmental concerns when used properly. Product development, testing and approval by the EPA takes from eight to 10 years and costs over $50 million (1990). This also leaves only about seven to nine years on the patent for the developer to recoup the costs.
Because of the importance for people to understand this process, this is the first part of a multi-part article on the general scheme for taking a compound out of a test tube to the crop. The article is based on my decade-long experience as a researcher in a chemical company and a brochure called "from Lab to Label" published by the American Crop Protection Association.
Phase I. Screening (Discovery)
Small quantities, as little as an ounce, of a compound is synthesized. The compound may be a derivative of another compound, an analog, or a foray into a new chemical sequence, or a by-product of a methodology used for something else, commonly a fermentation by-product. (The latter is the reason why most large ag-chemical manufacturers are closely related to a pharmaceutical manufacturer, such as Bayer.) In a large ag-chemical company 10 to 20 thousand compounds are made each year; exact numbers are kept confidential.
These compounds are tested routinely in special laboratory and greenhouse tests developed by the company's researchers. They are tested in these mini-screens for activity. The protocols for these tests are kept under trade secrets and change according to market development and interest.
After this initial screening, 100 to 500 of the 10-20,000 show some interesting activity warranting further testing in the greenhouse or insectary, etc. At this point, the first toxicological tests kick in. The most important and immediate test is the Ames mutagenicity test. This laboratory test on bacteria looks to see if the compound can alter DNA, normally by base substitution, and results are back in a few days. If it does, it's finished and will never leave the lab. The only testing permitted is by company researchers under highly protective conditions in the lab. This limited testing may be done by the researcher for various reasons, usually to define structure-activity relationships and look for non-mutagenic analogs.
If the compound passes this test, it will undergo an eye irritation test with a rabbit. This is a mild test and used as a guide for applicators. If the compounds might be tested other than locally at the research and development center, it must go through both oral and dermal toxicity tests on mice. This will determine the compounds LD50 or what is the dose for 50% mouse mortality when the compound is ingested or in skin contact. If the LD50s are acceptable, it is cleared for shipping in sealed packages.
About 100 to 500 compound per year are retested in the laboratory and greenhouse. These tests are designed to determine active rates and application timings, and determine the target pest and crop. Compound may be tested several times before going to the field for testing. Compounds that look promising are re-synthesized in slightly large quantities, 1 to 5 ounces.
This is the first field screening of compounds. Of the compounds tested in the secondary screen, 10 to 60 compounds will undergo small scale field tests. These tests are conducted initially on company research farms and are conducted in small plots. Application timing and method, rates, and some structure/activity tests are conducted. Analogs of active compounds are synthesized and tested in the secondary screens for activity and patent purposes. All of these analogs are also tested in the mutagenicity test and active ones are further put through the eye irritation, dermal toxicity and oral toxicity tests. From the initial field test, a few compounds, less than 10, are sent for testing by a few University researchers around the country in small plot evaluations to confirm the company's research and to determine activity in a wider range of situation.
At this time, the selected compounds undergo formulation testing. Formulation testing looks at different carriers and physical properties of the compounds. University researchers get test compounds in a preliminary formulation, usually a liquid flowable (LF), emulsifiable concentrate (EC) or wettable powder (WP). This is quite different than the form in the primary and secondary screens in which the compound is unformulated and tested in a solvent such as acetone.
At the same time, environmental impact testing begins on compounds going into tertiary screening. The compound's persistence in different soils and breakdown by soil microbes are key tests. Its volatilization and solar effects are measured. How it is metabolized by both the target crops and pests are determined using radio labeled tagging. The method of uptake, for instance root or foliar, and percent penetration and translocation are determined.
Toxicological testing is expanded to determine speed and amount mice excrete the compound, urine and feces. The metabolic breakdown of the compound in mice is determined, and all metabolic products are identified. These are called the "7-day toxicology studies" and a problem here, such as the formation of a dangerous by-product in the mouse, would eliminate the compound and possibly the whole chemistry from further testing.
In summary Phase II testing involves field efficacy trials, preliminary formulation studies, environmental persistence determinations, plant and/or pest metabolism, and rodent excretion and metabolism.
Of the 10-20,000 compounds that are screened each year (Phase I), only one to six go into Phase II Development.
Lab to Label: