Washington (CNN) -- GOP critics cranked up the political heat Thursday on Attorney General Eric Holder, threatening impeachment and accusing him of withholding information from Congress about Operation Fast and Furious, a severely flawed and discredited federal gun-sting program.
At the end of a long, combative day of testimony before the Republican-controlled House Judiciary Committee, California GOP Rep. Darrell Issa compared Holder to disgraced Nixon-era Attorney General John Mitchell.
Holder shot back by comparing Issa to Sen. Joe McCarthy, the infamous Wisconsin Republican censured by the Senate in 1954 for leading what critics called a Communist witch hunt.
"As they said in the McCarthy hearings, have you no shame?" asked Holder, referencing a famous retort to McCarthy.
Holder acknowledged mistakes were made, but said he would not resign over the controversy. The attorney general, accusing the GOP of playing political games, said he also didn't think any of his top aides should step down.
Operation Fast and Furious, which started in 2009, allowed illegally purchased firearms to be taken from gun stores in Arizona across the Mexican border to drug cartels. The intent of the operation was to monitor the flow of weapons to their ultimate destination.
However, hundreds of weapons were lost or unaccounted for, and a storm of outrage erupted when two of the missing weapons were found at a site where Border Patrol agent Brian Terry was killed in December 2010.
Democrats and Republicans have since been at odds over who knew what about the operation and when.
Wisconsin GOP Rep. Jim Sensenbrenner told Holder Thursday that "heads should roll" over the matter.
"There is really no responsibility within the Justice Department," Sensenbrenner said. "The thing is, if we don't get to the bottom of this -- and that requires your assistance on that -- there is only one alternative that Congress has and it is called impeachment."
Sensenbrenner did not make clear whether he was referring to the possible impeachment of Holder or other top Justice Department officials.
Blame for the botched operation "must go to your desk," Issa, the GOP's point man on investigating Fast and Furious, told Holder. Congress has been "systematically lied to" by department officials, he alleged.
For his part, Holder told committee members the operation relied on "unacceptable tactics" and was "inexcusable." But he insisted that Justice Department officials have cooperated with congressional investigators, and he said that any previous misleading information provided on the matter was not part of an intentional deception.
"It all has to do with your state of mind and whether or not you had the requisite intent to come up with something that can be considered perjury or (a) lie," Holder said.
The attorney general tried to turn the tables on his GOP critics, accusing them of engaging in "inflammatory and inappropriate rhetoric ... in an effort to score political points."
It's time to end "politically motivated 'gotcha' games," he said.
While Holder and his critics vehemently disagreed over the extent of executive-legislative cooperation in the Fast and Furious investigation, they agreed that the deadly fallout from the operation is not over.
Fast and Furious is "going to continue to have tragic consequences," Holder said at one point in Thursday's hearing.
"More people are going to die, probably," said Rep. Ted Poe, a Texas Republican.
"Unfortunately, I think that's probably true," Holder replied.
Last month, Holder testified before the Senate Judiciary Committee that the controversial operation "should never have happened, and ... must never happen again," hitting hard at the Bureau of Alcohol, Tobacco, Firearms and Explosives practice that has now tarnished his tenure at the Justice Department.
Despite Holder's insistence that Congress has never been intentionally misled in the matter, a number of Republicans have called for him to step down. Last month, Arizona Rep. Paul Gosar said the attorney general's "refusal to take responsibility for the actions of his department is inexcusable."
Earlier this week, Issa, head of the House Oversight and Government Reform Committee, said he is broadening his investigation to also include recent allegations of U.S. agents laundering money for Mexican cartels -- accusations that have infuriated officials on both sides of the border.
"These allegations, if true, raise further unsettling questions about a Department of Justice component engaging in a high-risk strategy with scant evidence of success," Issa said in a letter to Holder.
"The existence of such a program again calls your leadership into question," Issa added.
Sen. Charles Grassley, R-Iowa, said Wednesday that Assistant Attorney General Lanny Breuer should also resign because he misled Congress about his awareness of a February 4 letter that denied any gunrunning operation existed.
The Justice Department recently withdrew the letter due to inaccurate information, and Grassley said that e-mails turned over to congressional investigators showed Breuer saw various versions of the letter -- including the final one submitted to Congress -- before it was sent in February.
In addition, Grassley said Breuer knew in 2010 of a previous gunrunning operation by the ATF in the Bush administration, but he failed to notify superiors or Congress about it.
"Mr. Breuer's failure to be candid and forthcoming before this body irreparably harms his credibility," Grassley said, later adding: "Mr. Breuer has lost my confidence in his ability to effectively serve the Justice Department. If you can't be straight with the Congress you don't need to be running the Criminal Division. It is time to stop spinning and start taking responsibility."
In response, Justice Department spokeswoman Tracy Schmaler said Breuer "has acknowledged his mistake in not making -- and therefore not alerting department leadership to -- a connection between the allegations made about Operation Fast and Furious and the unacceptable tactics used years earlier."
But Holder "continues to have confidence" in Breuer's ability to lead the department's Criminal Division, Schmaler said.
Breuer and Holder previously apologized to a Senate committee and to Grassley in particular about the false information in the February letter. Both have insisted they did not know the assertions were wrong when the department sent the letter.
However, Grassley said Wednesday that the additional documents recently provided to congressional investigators show that Breuer should have been aware that the letter contained false assertions, due to his knowledge of a similar previous program called Operation Wide Receiver.
In Mexico, the case has drawn nationwide attention and sharp criticism from top officials, who have long stressed that U.S. weapons are fueling the country's drug war.
The Mexican attorney general's office demanded a quick U.S. investigation of the matter in March and said authorities must hold accountable anyone who was responsible for the operation.
CNN's Alan Silverleib, Tom Cohen, Terry Frieden and Jim Barnett contributed to this report.