ICHQ3C中PDE计算公式F4和F5取值如何理解

开心阿碧

如题所问。没有毒理学知识背景请教各位前辈。Q3C原文如下：
PDE is derived from the no-observed-effect level (NOEL), or the lowest-observed effect level (LOEL) in the most relevant animal study as follows:
               PDE =NOEL x Weight Adjustment/（F1 x F2 x F3 x F4 x F5）
The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be used. Modifying factors proposed here, for relating the data to humans, are the same kind of "uncertainty factors" used in Environmental Health Criteria (Environmental Health Criteria 170, World Health Organization, Geneva, 1994), and "modifying factors" or "safety factors" in Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all calculations regardless of route of administration.
F1、F2、F3 忽略
F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic
carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the
following factors are used:
  F4 = 1 for fetal toxicity associated with maternal toxicity
  F4 = 5 for fetal toxicity without maternal toxicity
  F4 = 5 for a teratogenic effect with maternal toxicity
  F4 = 10 for a teratogenic effect without maternal toxicity

F5 = A variable factor that may be applied if the no-effect level was not established
When only an LOEL is available, a factor of up to 10 could be used depending on the
severity of the toxicity.

问题1请教：F4应该如何理解（不是指中文翻译，是中文理解），什么情况下F4的取值是不同的。比如，下面的毒理数据中，F4的取值应该是多少？为什么？
XXX  was subcutaneously administered to pregnant mice at doses of15, 45, or 50μg/kg/day from GD 6-15. A slight reduction in food consumption and a dose-related reduction in body weight gain were noted in this study. However, XXX had no effect on fetal resorption, the number of live fetuses, or mean fetal weight. However, cleft palate was observed in 26 of 204 fetuses of the high dose group, and in 1 of 140 offspring of the intermediate dose group. Treatment with fluticasone propionate in this study also resulted in retarded cranialossification, as well as additional cranial sutural bones in offspring of the high dose group. Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 45 μg/kg/day). The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 15 μg/kg/day).


问题1请教：当知道NOEL值时，F5取值为1，还是可以是其他风险系数，比如2.5？，或者当无NOEL值，有LOEL值时，F5的取值是否可以是取5的风险系数，而不是10的风险系数？

443322

F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.
根据定义，当知道NOEL值时，F5取值为1。当只知道LOEL时，根据毒性进行评估，选取合适的数值。

443322

F4  无母体影响的致畸反应，选10.科学安全。

巴巴

请问没有NOEL和LD50是不是无法计算残留限度。现在很多只有NOAEL值，但NOAEL不等同于NOEL啊

cdyhuacai

巴巴 发表于 2021-6-8 15:06
请问没有NOEL和LD50是不是无法计算残留限度。现在很多只有NOAEL值，但NOAEL不等同于NOEL啊

NOEL和NOAEL我觉得可以通用

15851516352

巴巴 发表于 2021-6-8 15:06
请问没有NOEL和LD50是不是无法计算残留限度。现在很多只有NOAEL值，但NOAEL不等同于NOEL啊

个人感觉NOAEL是针对原料药的，NOEL是用于杂质的。计算原料药的PDE用NOAEL，杂质用NOEL

lpp122010909

巴巴 发表于 2021-6-8 15:06
请问没有NOEL和LD50是不是无法计算残留限度。现在很多只有NOAEL值，但NOAEL不等同于NOEL啊

两者等同，如果都没有，可以用LOAEL/LOEL