Prudent Planning of Experiments

Prudent execution of experiments requires not only sound judgment and an accurate assessment of the risks involved in laboratory work, but also the selection of appropriate work practices to reduce risk and protect the health and safety of the laboratory workers as well as the public and the environment. Chapter 3 provides specific guidelines to enable laboratory workers to evaluate the hazards and assess the risks associated with laboratory chemicals, equipment, and operations. Chapter 4 demonstrates how to control those risks when managing the inventory of chemicals in the laboratory. How the protocols outlined in Chapter 3 are put to use in the execution of a carefully planned experiment is the subject of Chapter 5. 

It is clear that no single, universally applicable description of "good" experiment planning exists and that the level of formality to be considered prudent in pre-experiment planning is a matter of judgment. In an area where potential hazards exist, more attention to planning is clearly better than less. 

Regulations are an intrinsic part of modern laboratory work that cannot be separated easily from other matters and should be considered at each step of experiment planning. It is only prudent for laboratory workers and supervisors to ensure regulatory compliance in conducting laboratory experiments. However, the responsibility of leadership goes beyond compliance to the protection of individual laboratory workers. 

Prudent management of chemicals in laboratories must begin long before the actual arrival of the chemicals. When experiments have been carefully planned, laboratory workers can be confident that they have chosen the procedures for working with chemicals that meet the following goals ... 

The initial conceptualization of the agelastatin A problem took on the form shown below (Scheme 5).17 The key transform in this sequence features intramolecular addition of an amide-derived anion to a tethered alkynyliodonium salt within 33. The alkylidenecarbene generated from this nucleophilic addition, 32, then has a choice of two diastereotopic C-H bonds (Ha or Hb) for 1,5 insertion. Reaction with Ha would provide an advanced intermediate 31 en route to the target 28. Successful execution of this plan would extend alkynyliodonium salt chemistry in three new directions (1) use of an amine derivative as a nucleophile, (2) intramolecularity in the nucleophile addition step, and (3) diastereoselectivity upon alkylidenecarbene C-H insertion. At the initiation of this project, a lack of precedent on any of these topics suggested that focused scouting experiments to assess feasibility would be prudent before beginning work towards the natural product itself. 

It is prudent to assume that sensitive material will explode at some time, but that one cannot predict when, and to plan experiments accordingly. It is thus necessary to adopt the practice of minimizing quantities, use distance or space between personnel and samples as well as protective barriers, avoid working with primary and high explosives in the same place, and in general practice good housekeeping. 

The cornerstone of a sound program for prudent laboratory practices is a process designed to comprehensively review the operations and potential hazards associated with each experiment over its life cycle. This review should take place before any work is conducted. The diverse nature of research and development activities makes it advisable to have such a process in place as part of the scientific method of experimentation. In laboratories where this preliminary survey is routinely practiced, it has proved to be useful in both the maintenance of safe laboratory operations and the minimization of chemical exposure and waste generation. Because of the diversity of types of researchers and laboratory work, such processes— both formal and informal—can help individuals associated with new, modified, or unfamiliar experiments or procedures to plan and work safely, responsibly, and productively. By first evaluating the work area, materials, equipment, and procedures in depth, hidden hazards may be identified and addressed. The pre-experiment review process can also help to ensure that every experiment and laboratory operation complies with all applicable laws, regulations, and other policies. Moreover, by addressing all relevant health, safety, and environmental issues when an experiment is first conceived, further research, scale-up, or development based on it can be made safer and more effective. 

The Material Safety Data Sheet (MSDS) for each hazardous chemical is one of the resources that should be incorporated into experiment planning. However, because of the inconsistent quality of information found in MSDSs, Laboratory Chemical Safety Summaries (LCSSs), which are compiled in Appendix B, should be consulted or developed for the materials involved. In any case, the experiment planner needs to be aware that the existing regulations do not necessarily represent the full complement of prudent practices for handling hazardous materials and that other input is therefore essential. 

Table 3.3 lists some of the most common chemicals with a high level of acute toxicity that are encounteed in the laboratory. These compounds must generally be handled using the additional procedures outlined in Chapter 5, section 5.D. In some circumstances, it may not be necessary to employ all of these special precautions, such as when the total amount of an acutely toxic substance to be handled is a small fraction of the harmful dose. It is an essential part of prudent experiment planning to determine whether a chemical with a high... 

Select appropriate procedures to minimize exposure. Use the "basic prudent practices for handling chemicals," which are discussed in Chapter 5, section 5.C, for all work with chemicals in the laboratory. In addition, determine whether any of the chemicals to be handled in the planned experiment meet the definition of a particularly hazardous substance due to high acute toxicity, carcinogenicity, and/ or reproductive toxicity. If so, consider the total amount of the substance that will be used, the expected frequency of use, the chemical s routes of exposure, and the circumstances of its use in the proposed experiment. As discussed in this chapter, use this information to determine whether it is appropriate to apply the additional procedures for work with highly toxic substances and whether additional consultation with safety professionals is warranted (see Chapter 5, section 5.D). 

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