Safe dose

Phase I. This involves general testing for human pharmacology in healthy volunteers, ie, safe-dose adjustment deterrnination of absorption, metabohsm, and excretion patterns and monitoring for side effects. Usually fewer than 10 test subjects ate involved. 

Chemical Contaminants (Carcinogens) If there is evidenee that a chemical may cause eancer, and there is no dose below which the chemieal is considered safe, the MCLG is set at zero. If a chemieal is carcinogenie and a safe dose can be deter mined, the MCLG is set at a level above zero that is safe. 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

BARNES s (2003) Phytoestrogens and osteoporosis - What is a safe dose Br J Nutr. in press. 

In pharmaceutical and medical device development, clinical trials are classified into four main phases designated with Roman numerals 1,11, III and lY The various phases of development trials differ in purpose, length and number of subjects involved. Phase I trials are conducted to determine safe dose levels of a medication, treatment or product (National Institutes of Health, 2002). The main purpose is often to determine an acceptable single dosage - how much can be given without causing serious side-effects. Phase I trials will also involve studies of metabolism and bioavailabity (Pocock, 1983). The sample size of a Phase 1 clinical trial is usually small, ranging from 10-80 subjects (National Institutes of Health, 2002 Pocock, 1983). 

Therefore, if human administration of MDMA-like compounds is considered clinically efficacious, further studies are needed to determine whether there may be a safe dose range or if there may be related compounds with less potential toxicity and similar beneficial effects. The studies reported here, and in other papers in this volume, describe several methodological approaches and well-characterized parameters to study the effects and... 

One important point of controversy in risk extrapolation is the existence of the threshold level for carcinogenic and mutagenic response to a pollutant. Some argue that an organism is able to cope with low doses of a substance through metabolic processes or repair mechanisms, so that harmful effects do not appear until a certain minimum threshold, or "safe dose", is surpassed. Others contend that a carcinogenic substance must be considered potentially harmful at any dose, and that even a single molecule may initiate a tumor at the cellular level. This is the so-called "one-hit" hypothesis. 

A report entitled Chemical Trespass was issued in May 2004 by the Pesticide Action Network (Schafer et al., 2006). It contained detailed analysis of 2000/01 National Health and Nutrition Examination Survey (NHANES) OP urinary metabolite data and used published methods to estimate exposure levels to parent compounds from creatinine corrected urinary metabolite levels. They focused on chlorpyrifos and its metabolite 3,4,6-trichloro-2-pyridinol (TCP), and found that chlorpyrifos exposures for children ages 6-11 and 12-19 exceeded EPA s chronic population-adjusted dose (cPAD) by surprisingly wide margins. Geometric mean TCP levels were 3 to 4.6 times higher than the EPA-estimated safe dose, as shown in Fig. 14.2. The more heavily exposed children received daily doses more than ten times the safe level. 

To convert to a dose or concentration of aniline that would cause an excess cancer risk of 10-4 (a virtually safe dose), the risk is divided by the slope factor dose=risk/slope... 

To convert a 70-y exposure to a 24-h exposure, the virtually safe dose is multiplied by the number of days in 70 yr ... 

Risk oflxlO-4=(lxlO-4/l)xl mg/m3=lxl0-4 mg/m3 (virtually safe dose). 

The acute toxicity of emorfazone was found to be equal to or less than that of aminopyrine depending on animal models used [45]. From chronic toxicity tests [46,47], safe doses of 30 mg/kg per day (rats) or 120 mg/kg per day (dogs) were deduced. In rats, no significant effects of (3) on the reproductive activity or newborn development were observed [48-50], nor were adverse effects on the embryos found when (3) was given to rabbits, rats or mice during the period... 

Toxicity studies should be designed not only to identify a safe dose, but also a toxic dose(s) to anticipate the product s safety and to better define the therapeutic index in humans. Specific product considerations that may complicate the process of defining a toxic dose may include limits based on formulation, lack of significant systemic absorption, or the amount of the product available. The lack of significant toxicity in animals does not necessarily mean that the product is safe. The margin of safety for the initial starting dose, however, will likely be adequate. 

In Pharmaceutical and Clinical Calculations, second edition, Drs. Mansoor Khan and Indra Reddy have provided a contemporary resource that can help pharmacy students learn the basic principles of how to accurately interpret prescriptions and medication orders, measure, calculate and compound quality dosage forms. In the latter chapters, the student can learn multiple methods to accurately and safely dose patients. The computational methods to accomplish these ends are clearly presented, and the examples used to demonstrate the concepts are relevant to contemporary practice. Pharmacy students will... 

The existence of the medical speciality of anesthesiology is itself an indication that inter-individual variation in anesthesia is important. As Nelson36 says in connection with anesthesia, "If a series is large enough there will inevitably be a number of dangerous or even fatal reactions from what are ordinarily considered safe doses." Of course,... 

Human exposures to cancer-producing chemicals (including pesticides) are uncontrolled and they are multiple.. .. It is quite possible that no one of these exposures alone would be sufficient to precipitate malignancy - yet any single supposedly safe dose may be enough to tip the scales that are already loaded with other safe doses. ... 

As stated at the outset of the section on threshold agents, risk is characterized (Step 4) by deriving what is sometimes called a hazard index, the ratio of known or expected doses incurred by the human population (Du) to the RfD, TDI, ADI, or MRL. A hazard index exceeding 1.0 suggests a risk that is, it can be taken to mean that some members of the population are exposed at levels exceeding the estimated population threshold. It is an unquantified risk, in two senses. First, although the RfD (or other estimates of safe dose) is considered... 

MAb-based constructs represent, as described, a heterogeneous class of anti-tumour agents with remarkable efficacy in the treatment of experimental cancers in animals. Several MAb and immunoconjugates have been evaluated further in cancer patients, and the results have indicated that some have activity at safe doses. 

The estimates of the parameters, qj and qi, are used to provide estimates either of the risks associated with specific doses, or conversely the dose associated with a specific increase in risk. The risk associated with a one in a million, 10 , extra lifetime incidence of cancer in the experimental species can be related to the dose this dose is often referred to as the Virtually Safe Dose (VSD). 

The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only 5-fold or less. Naltrexone does not appear to be a hepatotoxin at the recommended doses. 

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