Human challenge studies have ethical considerations because participants are often at risk of serious adverse effects, including death. There are many examples of trials that were problematic or abusive, such as trials on [[ConcentrationExperimentation camp#Nazion campsprisoners|trials on captives]] under the [[Nazi Germany|Nazi regime]] in [[Germany]] or trials with questionable consent procedures in [[Guatemala]] by U.S. doctor [[John Charles Cutler]], who also conducted the [[Tuskegee Syphilis Experiment]].<ref>{{Cite journal|last1=Metzger|first1=W. G.|last2=Ehni|first2=H.-J.|last3=Kremsner|first3=P. G.|last4=Mordmüller|first4=B. G.|date=2019|title=Experimental infections in humans—historical and ethical reflections|journal=Tropical Medicine & International Health|language=en|volume=24|issue=12|pages=1384–1390|doi=10.1111/tmi.13320|pmid=31654450|issn=1365-3156|doi-access=free}}</ref> Special ethical issues can arise when a wealthy country finances and organizes these clinical trials in a less wealthy country.<ref>{{cite journal |last1=Gordon |first1=SB |last2=Rylance |first2=J |last3=Luck |first3=A |last4=Jambo |first4=K |last5=Ferreira |first5=DM |last6=Manda-Taylor |first6=L |last7=Bejon |first7=P |last8=Ngwira |first8=B |last9=Littler |first9=K |last10=Seager |first10=Z |last11=Gibani |first11=M |last12=Gmeiner |first12=M |last13=Roestenberg |first13=M |last14=Mlombe |first14=Y |last15=Wellcome Trust CHIM workshop |first15=participants. |title=A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi. |journal=Wellcome Open Research |date=2017 |volume=2 |pages=70 |doi=10.12688/wellcomeopenres.12256.1 |pmid=29018841|pmc=5627502 |doi-access=free }}</ref>
Two commonly discussed general thresholds for risk to research participant are minimizing all risk after the infection and avoiding serious injury.<ref name="Binik 2020">{{cite journal |last1=Binik |first1=Ariella |title=What risks should be permissible in controlled human infection model studies? |journal=Bioethics |date=May 2020 |volume=34 |issue=4 |pages=420–430 |doi=10.1111/bioe.12736|pmid=32115747 |s2cid=211727412 }}</ref> Researchers typically customize other thresholds for each clinical trial.<ref name="Binik 2020"/>
